Is LEPR p.Val581Ala (c.1742T>C) pathogenic?

LEPR p.Val581Ala (c.1742T>C) is classified Uncertain significance in LEPR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-08). AlphaMissense: likely benign (0.1456); Very rare (popmax 0.0011%, sas).

How common is LEPR p.Val581Ala (c.1742T>C) in the general population?

LEPR p.Val581Ala (c.1742T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about LEPR p.Val581Ala (c.1742T>C)?

AlphaMissense predicts likely benign (score 0.1456) — an in-silico prediction, not a clinical call.

LEPR p.Val581Ala

c.1742T>C · rs2100964693 · VCV1337853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1456 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1456	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	donor gain, 10 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.1	GERP 0.28, phastCons 0.011
Regional constraint	o/e 0.89	unconstrained · MANE · 71 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	15.41	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 0.0011% South Asian · 1/91,042 alleles

Overall 6.2e-05% 1/1,613,698 alleles · very rare exomes 1/1,461,378 · genomes 0/152,320 · 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: LEPR
Protein: p.Val581Ala
Coding: c.1742T>C
MANE Select: NM_002303
dbSNP: rs2100964693
Type: single nucleotide variant
Location: chr1:65608891 (GRCh38)
Gene constraint: LOEUF 0.589 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.49 · 9 PDB
Residue 581: the fibronectin type-iii 2 domain

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

Similar variants

LEPR c.995-2A>G Likely pathogenic ★★ same type
LEPR p.Trp31Ter Pathogenic ★★ same type
LEPR p.Ala545= Uncertain significance ★★ same type
LEPR p.Arg678Ser Uncertain significance ★★ ⚠ same type
LEPR p.Asn397Lys Uncertain significance ★★ ⚠ same type
LEPR p.Glu565Asp Uncertain significance ★★ ⚠ same type
LEPR p.Ile1085Val Uncertain significance ★★ ⚠ same type
LEPR p.Ile551Asn Uncertain significance ★★ ⚠ same type

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/lepr-p-val581ala (accessed [today's date]).

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