Is GEMIN4 p.Ser755Phe (c.2264C>T) pathogenic?

GEMIN4 p.Ser755Phe (c.2264C>T) is classified Uncertain significance in GEMIN4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-01-15). AlphaMissense: likely pathogenic (0.8368); Ultra-rare (popmax 0.0494%, mid); Associated with neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities.

How common is GEMIN4 p.Ser755Phe (c.2264C>T) in the general population?

GEMIN4 p.Ser755Phe (c.2264C>T) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

What do computational predictors say about GEMIN4 p.Ser755Phe (c.2264C>T)?

AlphaMissense predicts likely pathogenic (score 0.8368) — an in-silico prediction, not a clinical call.

GEMIN4 p.Ser755Phe

Q: What condition is associated with GEMIN4 p.Ser755Phe (c.2264C>T)?

GEMIN4 p.Ser755Phe (c.2264C>T) is associated with neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities (ClinVar).

c.2264C>T · rs369869667 · VCV1027999

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8368 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities

Computational evidence

Protein change
AlphaMissense	0.8368	likely pathogenic
REVEL	0.472	indeterminate
SaProt	LLR -10.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,807 bp · p 0.23 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0494% Middle Eastern · 3/6,078 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00118% 19/1,612,068 alleles · ultra-rare exomes 17/1,459,886 · genomes 2/152,182 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,026
European (non-Finnish)	0.00136%	73,706

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.Ser755Phe
Coding: c.2264C>T
MANE Select: NM_015721
dbSNP: rs369869667
Type: single nucleotide variant
Location: chr17:745779 (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

Disease context

neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GEMIN4 p.Trp818Arg Pathogenic/Likely pathogenic ★★ same condition
GEMIN4 p.Ala186Val Uncertain significance ★★ ⚠ same condition
GEMIN4 p.Arg91Gln Uncertain significance ★★ ⚠ same condition
GEMIN4 p.Gln1032Ter Uncertain significance ★★ same condition
GEMIN4 c.10+80C>T Benign ★★ same condition
GEMIN4 p.Ala579Gly Benign ★★ same condition
GEMIN4 p.Arg1033Cys Benign ★★ same condition
GEMIN4 p.Arg684Gln Benign ★★ 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/gemin4-p-ser755phe (accessed [today's date]).

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