Is LDLR p.Cys338Ser (c.1012T>A) pathogenic?

LDLR p.Cys338Ser (c.1012T>A) is classified Pathogenic/Likely pathogenic in LDLR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-19). AlphaMissense: likely pathogenic (0.9979); Very rare (popmax 0.00223%, eas); Associated with familial hypercholesterolemia.

What condition is associated with LDLR p.Cys338Ser (c.1012T>A)?

LDLR p.Cys338Ser (c.1012T>A) is associated with familial hypercholesterolemia, hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Cys338Ser (c.1012T>A) in the general population?

LDLR p.Cys338Ser (c.1012T>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about LDLR p.Cys338Ser (c.1012T>A)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

LDLR p.Cys338Ser

c.1012T>A · rs879254753 · VCV251592

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypercholesterolemia

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic ✓ concordant with ClinVar · top 1% in LDLR
REVEL	0.927	moderately pathogenic-leaning
SaProt	LLR -12.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	24.6	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 0.00223% East Asian · 1/44,870 alleles

Overall 6.84e-05% 1/1,461,592 alleles · very rare

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.Cys338Ser
Coding: c.1012T>A
MANE Select: NM_000527
dbSNP: rs879254753
Type: single nucleotide variant
Location: chr19:11110723 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 338: the egf-like 1 domain; a UniProt-annotated variant site (in fhcl1); a β-strand; a disulfide bond

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

Also linked: hypercholesterolemia, familial, 1

Similar variants

LDLR p.Cys338Gly Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys338Phe Likely pathogenic ★★ same residue
LDLR p.Cys338Tyr Pathogenic/Likely pathogenic ★★ same residue
LDLR p.Cys338= Likely benign ★★ same residue
LDLR p.Cys338Arg Likely pathogenic ★ same residue
LDLR p.Cys338Ter Pathogenic ★ same residue
LDLR p.Cys338Trp Pathogenic same residue
LDLR c.1186+5G>A Likely 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-cys338ser (accessed [today's date]).

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