Is LEPR p.Ile28Val (c.82A>G) pathogenic?

LEPR p.Ile28Val (c.82A>G) is classified Uncertain significance in LEPR (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-08). AlphaMissense: likely benign (0.0673); Ultra-rare (popmax 0.02%, afr).

How common is LEPR p.Ile28Val (c.82A>G) in the general population?

LEPR p.Ile28Val (c.82A>G) is ultra-rare (popmax 0.02%, afr) (gnomAD).

What do computational predictors say about LEPR p.Ile28Val (c.82A>G)?

AlphaMissense predicts likely benign (score 0.0673) — an in-silico prediction, not a clinical call.

LEPR p.Ile28Val

c.82A>G · rs369475236 · VCV2443479

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0673 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0673	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.68	acceptor gain · deltas
Pangolin	Δ0.57	gain · loss 0.21 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.4	GERP -3.4
Regional constraint	o/e 0.89	unconstrained · MANE · 71 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	14.49	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 0.02% African / African-American · 15/74,918 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00989%

Overall 0.00149% 24/1,613,792 alleles · ultra-rare exomes 17/1,461,586 · genomes 7/152,206 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,995
Middle Eastern	0.0164%	6,080
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.000593%	168,562

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.Ile28Val
Coding: c.82A>G
MANE Select: NM_002303
dbSNP: rs369475236
Type: single nucleotide variant
Location: chr1:65570514 (GRCh38)
Gene constraint: LOEUF 0.589 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.49 · 9 PDB

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-ile28val (accessed [today's date]).

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