Is JAM3 p.Val251Phe (c.751G>T) pathogenic?

JAM3 p.Val251Phe (c.751G>T) is classified Uncertain significance in JAM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-20). AlphaMissense: ambiguous (0.3772); Very rare (popmax 0.00127%, nfe).

How common is JAM3 p.Val251Phe (c.751G>T) in the general population?

JAM3 p.Val251Phe (c.751G>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about JAM3 p.Val251Phe (c.751G>T)?

AlphaMissense predicts ambiguous (score 0.3772) — an in-silico prediction, not a clinical call.

JAM3 p.Val251Phe

c.751G>T · rs761535214 · VCV1506907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3772 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3772	ambiguous
REVEL	0.776	moderately pathogenic-leaning
SaProt	LLR -8.73	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.7, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 80 kb · p 0.0013 · regional, not allelic
Overall
CADD	27.3	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 0.00127% European (non-Finnish) · 15/1,180,028 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000991% 16/1,614,138 alleles · very rare exomes 16/1,461,894 · genomes 0/152,244 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)grpmax	0.00127%	78,668

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: JAM3
Protein: p.Val251Phe
Coding: c.751G>T
MANE Select: NM_032801
dbSNP: rs761535214
Type: single nucleotide variant
Location: chr11:134148585 (GRCh38)
Gene constraint: LOEUF 1.003 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.67

Full JAM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

JAM3 c.612+1G>T Pathogenic ★★ same type
JAM3 p.Ala2Ser Uncertain significance ★★ ⚠ same type
JAM3 p.Arg107Trp Uncertain significance ★★ same type
JAM3 p.Arg123Cys Uncertain significance ★★ ⚠ same type
JAM3 p.Arg14Trp Uncertain significance ★★ ⚠ same type
JAM3 p.Arg168Gln Uncertain significance ★★ ⚠ same type
JAM3 p.Arg185Ile Uncertain significance ★★ ⚠ same type
JAM3 p.Arg191Cys 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/jam3-p-val251phe (accessed [today's date]).

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