Is LEPR p.Ala458Val (c.1373C>T) pathogenic?

LEPR p.Ala458Val (c.1373C>T) is classified Likely benign in LEPR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-17). AlphaMissense: likely benign (0.0693); Ultra-rare (popmax 0.0401%, afr); Associated with Inborn genetic diseases.

What condition is associated with LEPR p.Ala458Val (c.1373C>T)?

LEPR p.Ala458Val (c.1373C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LEPR p.Ala458Val (c.1373C>T) in the general population?

LEPR p.Ala458Val (c.1373C>T) is ultra-rare (popmax 0.0401%, afr) (gnomAD).

What do computational predictors say about LEPR p.Ala458Val (c.1373C>T)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

LEPR p.Ala458Val

c.1373C>T · rs138922570 · VCV2065970

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -6.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.79	GERP -1.2
Regional constraint	o/e 0.89	unconstrained · MANE · 71 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	0.21	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 0.0401% African / African-American · 30/74,842 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.025%

Overall 0.00242% 39/1,613,410 alleles · ultra-rare exomes 22/1,461,424 · genomes 17/151,986 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0401%	2,495
South Asian	0.0022%	45,538
European (non-Finnish)	0.000593%	168,516

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.Ala458Val
Coding: c.1373C>T
MANE Select: NM_002303
dbSNP: rs138922570
Type: single nucleotide variant
Location: chr1:65601930 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LEPR p.Ala458= Uncertain significance ★ same residue
LEPR p.Ala458Glu Uncertain significance ★ ⚠ same residue
LEPR p.Arg678Ser Uncertain significance ★★ ⚠ same condition
LEPR p.Asn397Lys Uncertain significance ★★ ⚠ same condition
LEPR p.Glu565Asp Uncertain significance ★★ ⚠ same condition
LEPR p.Ile1085Val Uncertain significance ★★ ⚠ same condition
LEPR p.Ile551Asn Uncertain significance ★★ ⚠ same condition
LEPR p.Leu471Ile Uncertain significance ★★ ⚠ 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/lepr-p-ala458val (accessed [today's date]).

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