Is LEPR p.Ser435Pro (c.1303T>C) pathogenic?

LEPR p.Ser435Pro (c.1303T>C) is classified Uncertain significance in LEPR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-01). AlphaMissense: likely pathogenic (0.736); Very rare (popmax 0.0011%, nfe); Associated with LEPR-related disorder.

What condition is associated with LEPR p.Ser435Pro (c.1303T>C)?

LEPR p.Ser435Pro (c.1303T>C) is associated with LEPR-related disorder (ClinVar).

How common is LEPR p.Ser435Pro (c.1303T>C) in the general population?

LEPR p.Ser435Pro (c.1303T>C) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about LEPR p.Ser435Pro (c.1303T>C)?

AlphaMissense predicts likely pathogenic (score 0.736) — an in-silico prediction, not a clinical call.

LEPR p.Ser435Pro

c.1303T>C · VCV3355085

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.736 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

LEPR-related disorder

Computational evidence

Protein change
AlphaMissense	0.736	likely pathogenic · top 8% in LEPR
REVEL	0.274	benign-leaning
SaProt	LLR -13.90	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 71 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	25.5	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 0.0011% European (non-Finnish) · 13/1,179,342 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000806% 13/1,613,146 alleles · very rare exomes 12/1,461,044 · genomes 1/152,102 · 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.Ser435Pro
Coding: c.1303T>C
MANE Select: NM_002303
Type: single nucleotide variant
Location: chr1:65601860 (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 435: a β-strand

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

Disease context

LEPR-related disorder

Similar variants

LEPR c.2213-2A>G Likely pathogenic ★ same condition
LEPR p.Pro316Thr Likely pathogenic ★ ⚠ same condition
LEPR p.Thr661Ala Likely pathogenic ★ ⚠ same condition
LEPR p.Trp664Arg Pathogenic ★ same condition
LEPR p.Ala458Glu Uncertain significance ★ ⚠ same condition
LEPR p.Gln177= Uncertain significance ★ same condition
LEPR p.Gly179Asp Conflicting classifications of pathogenicity ★ ⚠ same condition
LEPR p.Met1160Val 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-ser435pro (accessed [today's date]).

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