Is LDLR p.Ala391= (c.1173C>T) pathogenic?

LDLR p.Ala391= (c.1173C>T) is classified Likely benign in LDLR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-05). Very rare (popmax 0.00102%, nfe); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Ala391= (c.1173C>T)?

LDLR p.Ala391= (c.1173C>T) is associated with familial hypercholesterolemia (ClinVar).

How common is LDLR p.Ala391= (c.1173C>T) in the general population?

LDLR p.Ala391= (c.1173C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

LDLR p.Ala391=

c.1173C>T · rs1293318775 · VCV2773508

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.71	GERP -2.3, phastCons 0.17
Overall
CADD	9.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,179,908 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000806% 13/1,613,466 alleles · very rare exomes 12/1,461,248 · genomes 1/152,218 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)grpmax	0.00102%	98,326

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala391=
Coding: c.1173C>T
MANE Select: NM_000527
dbSNP: rs1293318775
Type: single nucleotide variant
Location: chr19:11111626 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 391: the egf-like 2; calcium-binding domain; a UniProt-annotated variant site (in)

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

Disease context

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

Similar variants

LDLR p.Ala391Thr Benign ★★★ same residue
LDLR p.Ala391Pro Uncertain significance ★ same residue
LDLR p.Ala391fs 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.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-ala391 (accessed [today's date]).

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