Is GCM2 p.Pro256Ser (c.766C>T) pathogenic?

GCM2 p.Pro256Ser (c.766C>T) is classified Uncertain significance in GCM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-07). AlphaMissense: likely benign (0.0811); Absent from gnomAD v4.1.

How common is GCM2 p.Pro256Ser (c.766C>T) in the general population?

GCM2 p.Pro256Ser (c.766C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GCM2 p.Pro256Ser (c.766C>T)?

AlphaMissense predicts likely benign (score 0.0811) — an in-silico prediction, not a clinical call.

GCM2 p.Pro256Ser

c.766C>T · VCV4778746

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0811 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0811	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -5.87	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 3.8	GERP -0.27, phastCons 0.7
Regional constraint	o/e 0.83	unconstrained · MANE · 3,221 bp · p 0.00012 · regional, not allelic
Overall
CADD	9.668	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GCM2
Protein: p.Pro256Ser
Coding: c.766C>T
MANE Select: NM_004752
Type: single nucleotide variant
Location: chr6:10874750 (GRCh38)
Gene constraint: LOEUF 1.205 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.78
Residue 256: a UniProt-annotated variant site (in fih2; transcription of mrna, but loss of protein expression)

Full GCM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GCM2 c.90+2T>G Likely pathogenic ★★ same type
GCM2 p.Arg47Leu Pathogenic ★★ same type
GCM2 p.Arg67Cys Likely pathogenic ★★ same type
GCM2 p.Tyr136Ter Pathogenic ★★ same type
GCM2 c.*217T>A Uncertain significance ★★ same type
GCM2 p.Ala148Val Uncertain significance ★★ ⚠ same type
GCM2 p.Ala180Pro Uncertain significance ★★ ⚠ same type
GCM2 p.Ala355Thr 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/gcm2-p-pro256ser (accessed [today's date]).

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