Is LDLR p.Ala50Ser (c.148G>T) pathogenic?

LDLR p.Ala50Ser (c.148G>T) is classified Uncertain significance in LDLR (ClinVar, Expert panel, 29 submitters; last evaluated 2024-10-28). AlphaMissense: likely benign (0.0818); Ultra-rare (popmax 0.0774%, nfe); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Ala50Ser (c.148G>T)?

LDLR p.Ala50Ser (c.148G>T) is associated with hypercholesterolemia, familial, 1, familial hypercholesterolemia (ClinVar).

How common is LDLR p.Ala50Ser (c.148G>T) in the general population?

LDLR p.Ala50Ser (c.148G>T) is ultra-rare (popmax 0.0774%, nfe) (gnomAD).

What do computational predictors say about LDLR p.Ala50Ser (c.148G>T)?

AlphaMissense predicts likely benign (score 0.0818) — an in-silico prediction, not a clinical call.

LDLR p.Ala50Ser

c.148G>T · rs137853960 · VCV68099

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 29 submitters

AlphaMissense

likely benign

0.0818 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0774%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypercholesterolemia, familial, 1

ClinGen expert panel

Uncertain Significance — Familial Hypercholesterolemia VCEP (hypercholesterolemia, familial).

Computational evidence

Protein change
AlphaMissense	0.0818	likely benign
REVEL	0.545	indeterminate
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.7	GERP -4.8
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	0.058	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 0.0774% European (non-Finnish) · 913/1,179,912 alleles

Filtering AF 0.0732% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0715%

Overall 0.0613% 990/1,613,768 alleles · ultra-rare exomes 923/1,461,492 · genomes 67/152,276 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0774%	1,292
Admixed American	0.0517%	1,936
Remaining individualsnot grpmax-eligible	0.0352%	2,841
Finnishnot grpmax-eligible	0.0235%	4,251
African / African-American	0.012%	8,338

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.Ala50Ser
Coding: c.148G>T
MANE Select: NM_000527
dbSNP: rs137853960
Type: single nucleotide variant
Location: chr19:11100303 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 50: the ldl-receptor class a 1 domain; a UniProt-annotated variant site (in fhcl1); a UniProt-annotated variant site (in fhcl1; uncertain significance)

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.Ala50Thr Uncertain significance ★★★ ⚠ same residue
LDLR p.Ala50= Likely benign ★★ same residue
LDLR p.Ala50Gly Uncertain significance ★ ⚠ same residue
LDLR p.Ala50fs 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

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-ala50ser (accessed [today's date]).

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