Is LEPR p.Val984Phe (c.2950G>T) pathogenic?

LEPR p.Val984Phe (c.2950G>T) is classified Uncertain significance in LEPR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: likely benign (0.2204); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LEPR p.Val984Phe (c.2950G>T)?

LEPR p.Val984Phe (c.2950G>T) is associated with Inborn genetic diseases (ClinVar).

How common is LEPR p.Val984Phe (c.2950G>T) in the general population?

LEPR p.Val984Phe (c.2950G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about LEPR p.Val984Phe (c.2950G>T)?

AlphaMissense predicts likely benign (score 0.2204) — an in-silico prediction, not a clinical call.

LEPR p.Val984Phe

c.2950G>T · VCV4046901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2204 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2204	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -6.47	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 71 kb · p 4.1e-05 · regional, not allelic
Overall
CADD	22.6	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 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 6.2e-05% 1/1,613,938 alleles · very rare exomes 0/1,461,780 · genomes 1/152,158 · 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.Val984Phe
Coding: c.2950G>T
MANE Select: NM_002303
Type: single nucleotide variant
Location: chr1:65636467 (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

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LEPR p.Ile1085Val Uncertain significance ★★ ⚠ same condition
LEPR p.Ile551Asn Uncertain significance ★★ ⚠ same condition
LEPR p.Leu471Ile Uncertain significance ★★ ⚠ same condition
LEPR p.Pro1068Arg Uncertain significance ★★ ⚠ same condition
LEPR p.Pro231Ser 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-val984phe (accessed [today's date]).

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