Is GEMIN4 p.Val656Phe (c.1966G>T) pathogenic?

GEMIN4 p.Val656Phe (c.1966G>T) is classified Uncertain significance in GEMIN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: likely pathogenic (0.7184); Ultra-rare (popmax 0.0177%, nfe).

How common is GEMIN4 p.Val656Phe (c.1966G>T) in the general population?

GEMIN4 p.Val656Phe (c.1966G>T) is ultra-rare (popmax 0.0177%, nfe) (gnomAD).

What do computational predictors say about GEMIN4 p.Val656Phe (c.1966G>T)?

AlphaMissense predicts likely pathogenic (score 0.7184) — an in-silico prediction, not a clinical call.

GEMIN4 p.Val656Phe

c.1966G>T · rs200818121 · VCV2373549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7184 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0177%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7184	likely pathogenic
REVEL	0.524	indeterminate
SaProt	LLR -9.71	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,807 bp · p 0.23 · regional, not allelic
Overall
CADD	24.6	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 0.0177% European (non-Finnish) · 209/1,179,898 alleles

Filtering AF 0.0157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.015%

Overall 0.0136% 220/1,613,968 alleles · ultra-rare exomes 207/1,461,654 · genomes 13/152,314 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0177%	5,645
Remaining individualsnot grpmax-eligible	0.008%	12,497
African / African-American	0.00666%	15,008
Admixed American	0.00167%	60,024

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: GEMIN4
Protein: p.Val656Phe
Coding: c.1966G>T
MANE Select: NM_015721
dbSNP: rs200818121
Type: single nucleotide variant
Location: chr17:746077 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.54

Full GEMIN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GEMIN4 p.Trp818Arg Pathogenic/Likely pathogenic ★★ same type
GEMIN4 p.Ala186Val Uncertain significance ★★ ⚠ same type
GEMIN4 p.Arg91Gln Uncertain significance ★★ ⚠ same type
GEMIN4 p.Gln1032Ter Uncertain significance ★★ same type
GEMIN4 p.Gly814Glu Uncertain significance ★★ ⚠ same type
GEMIN4 p.Ile406Val Uncertain significance ★★ ⚠ same type
GEMIN4 p.Leu178Val Uncertain significance ★★ ⚠ same type
GEMIN4 p.Ser755Phe 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/gemin4-p-val656phe (accessed [today's date]).

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