Is LDLR p.Val797Met (c.2389G>A) pathogenic?

LDLR p.Val797Met (c.2389G>A) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 28 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.167); Very rare (popmax 0.00446%, eas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Val797Met (c.2389G>A)?

LDLR p.Val797Met (c.2389G>A) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia, homozygous familial hypercholesterolemia (ClinVar).

How common is LDLR p.Val797Met (c.2389G>A) in the general population?

LDLR p.Val797Met (c.2389G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about LDLR p.Val797Met (c.2389G>A)?

AlphaMissense predicts likely benign (score 0.167) — an in-silico prediction, not a clinical call.

LDLR p.Val797Met

c.2389G>A · rs750518671 · VCV226393

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 28 submitters

AlphaMissense

likely benign

0.167 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.167	likely benign ⚠ discordant with ClinVar
REVEL	0.599	indeterminate
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.32	donor loss · deltas
Pangolin	Δ0.31	loss · gain 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,872 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000434% 7/1,613,688 alleles · very rare exomes 5/1,461,610 · genomes 2/152,078 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,436
South Asian	0.00329%	30,361
Admixed American	0.00167%	59,974
African / African-American	0.00134%	74,894

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.Val797Met
Coding: c.2389G>A
MANE Select: NM_000527
dbSNP: rs750518671
Type: single nucleotide variant
Location: chr19:11128085 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 797: a UniProt-annotated variant site (in fhcl1)

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 homozygous familial hypercholesterolemia

Similar variants

LDLR p.Val797Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
LDLR p.Val797= Likely benign ★ 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-val797met (accessed [today's date]).

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