Is GEMIN4 p.Arg445Ser (c.1335G>C) pathogenic?

GEMIN4 p.Arg445Ser (c.1335G>C) is classified Uncertain significance in GEMIN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-17). AlphaMissense: likely benign (0.2372); Ultra-rare (popmax 0.0483%, sas).

How common is GEMIN4 p.Arg445Ser (c.1335G>C) in the general population?

GEMIN4 p.Arg445Ser (c.1335G>C) is ultra-rare (popmax 0.0483%, sas) (gnomAD).

What do computational predictors say about GEMIN4 p.Arg445Ser (c.1335G>C)?

AlphaMissense predicts likely benign (score 0.2372) — an in-silico prediction, not a clinical call.

GEMIN4 p.Arg445Ser

c.1335G>C · rs558481262 · VCV3099342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2372 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2372	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -6.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.13	GERP -0.65
Regional constraint	o/e 1.04	unconstrained · MANE · 2,807 bp · p 0.23 · regional, not allelic
Overall
CADD	16.88	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 0.0483% South Asian · 44/91,084 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00291% 47/1,613,596 alleles · ultra-rare exomes 44/1,461,350 · genomes 3/152,246 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0483%	2,070
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	8.48e-05%	1,179,884

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.Arg445Ser
Coding: c.1335G>C
MANE Select: NM_015721
dbSNP: rs558481262
Type: single nucleotide variant
Location: chr17:746708 (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.Arg445Gly Uncertain significance ★ ⚠ same residue
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

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-arg445ser (accessed [today's date]).

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