Is LDLR p.Val271Ile (c.811G>A) pathogenic?

LDLR p.Val271Ile (c.811G>A) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 8 submitters; last evaluated 2023-06-23). AlphaMissense: likely benign (0.0749); Ultra-rare (popmax 0.0164%, mid); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Val271Ile (c.811G>A)?

LDLR p.Val271Ile (c.811G>A) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Val271Ile (c.811G>A) in the general population?

LDLR p.Val271Ile (c.811G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about LDLR p.Val271Ile (c.811G>A)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

LDLR p.Val271Ile

c.811G>A · rs749220643 · VCV189297

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel — Familial Hypercholesterolemia VCEP

Uncertain Significance for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):

PM2 PP1 PP4 BP4

Curation rationale (ClinGen, verbatim)

The NM_000527.5(LDLR):c.811G>A (p.Val271Ile) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP4, and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00011 (0.011%) in East Asian exomes+genomes (gnomAD v2.1.1). BP4: REVEL=0.33. It is below 0.5, splicing evaluation required. Functional data on splicing not available. A) not on limits. B) does not create GT. C) there is no GT nearby. Variant is not predicted to alter splicing. PP1: Variant segregates with FH phenotype in 3 informative meioses in 1 family from PMID 26036859 (Brænne I et al., 2016). 2 affected family members have the variant. PP4: Variant meets PM2 and is identified in 1 index case with DLCN score >=6 from PMID 26036859 (Brænne I et al., 2016: LDL-C 286 mg/dl and a history of premature CAD, DLCN=7).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.4	GERP -3.7
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	0.009	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000991% 16/1,614,022 alleles · ultra-rare exomes 15/1,461,838 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00668%	14,963
South Asian	0.00329%	30,363
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	0.000593%	168,574

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: LDLR
Protein: p.Val271Ile
Coding: c.811G>A
MANE Select: NM_000527
dbSNP: rs749220643
Type: single nucleotide variant
Location: chr19:11106681 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 271: the ldl-receptor class a 6 domain

Full LDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypercholesterolemia, familial, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypercholesterolemia

Similar variants

LDLR p.Val271fs Pathogenic ★★ same residue
LDLR p.Val271_Asn272insTer Pathogenic ★ same residue
LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
LDLR c.1359-1G>A Pathogenic ★★★ same condition
LDLR c.1359-5C>G Likely pathogenic ★★★ same condition
LDLR c.1705+2T>C Likely pathogenic ★★★ same condition
LDLR c.190+4A>T Likely pathogenic ★★★ same condition
LDLR c.2140+1G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ldlr-p-val271ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown