Is LDLR p.Ser41Thr (c.121T>A) pathogenic?

LDLR p.Ser41Thr (c.121T>A) is classified Uncertain significance in LDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.1955); Ultra-rare (popmax 0.0178%, eas); Associated with hypercholesterolemia, familial, 1.

What condition is associated with LDLR p.Ser41Thr (c.121T>A)?

LDLR p.Ser41Thr (c.121T>A) is associated with hypercholesterolemia, familial, 1 (ClinVar).

How common is LDLR p.Ser41Thr (c.121T>A) in the general population?

LDLR p.Ser41Thr (c.121T>A) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about LDLR p.Ser41Thr (c.121T>A)?

AlphaMissense predicts likely benign (score 0.1955) — an in-silico prediction, not a clinical call.

LDLR p.Ser41Thr

c.121T>A · rs2077193859 · VCV889189

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1955 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypercholesterolemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.1955	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -8.95	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 2.5	GERP -2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 42 kb · p 0.91 · regional, not allelic
Overall
CADD	12.55	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 0.0178% East Asian · 8/44,888 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000496% 8/1,613,892 alleles · ultra-rare exomes 8/1,461,620 · genomes 0/152,272 · joint denominator

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.Ser41Thr
Coding: c.121T>A
MANE Select: NM_000527
dbSNP: rs2077193859
Type: single nucleotide variant
Location: chr19:11100276 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 36 PDB
Residue 41: a β-strand; the ldl-receptor class a 1 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

Similar variants

LDLR p.Ser41= Likely benign ★ same residue
LDLR p.Ser41Phe Uncertain significance ★ 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-ser41thr (accessed [today's date]).

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