Is GEMIN4 p.Pro85Ser (c.253C>T) pathogenic?

GEMIN4 p.Pro85Ser (c.253C>T) is classified Uncertain significance in GEMIN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). AlphaMissense: likely benign (0.0686); Ultra-rare (popmax 0.0208%, nfe).

How common is GEMIN4 p.Pro85Ser (c.253C>T) in the general population?

GEMIN4 p.Pro85Ser (c.253C>T) is ultra-rare (popmax 0.0208%, nfe) (gnomAD).

What do computational predictors say about GEMIN4 p.Pro85Ser (c.253C>T)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

GEMIN4 p.Pro85Ser

c.253C>T · rs146489979 · VCV2519665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0208%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -5.85	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 2.2	GERP 1.2, phastCons 0.99
Regional constraint	o/e 0.68	unconstrained · MANE · 4,465 bp · p 7e-05 · regional, not allelic
Overall
CADD	2.779	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 0.0208% European (non-Finnish) · 245/1,179,756 alleles

Filtering AF 0.0186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0178%

Overall 0.0162% 261/1,613,496 alleles · ultra-rare exomes 245/1,461,494 · genomes 16/152,002 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0208%	4,815
East Asian	0.0156%	6,406
Remaining individualsnot grpmax-eligible	0.0064%	15,617
African / African-American	0.004%	24,978
Admixed American	0.00334%	29,975

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.Pro85Ser
Coding: c.253C>T
MANE Select: NM_015721
dbSNP: rs146489979
Type: single nucleotide variant
Location: chr17:747790 (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-pro85ser (accessed [today's date]).

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