Is GCM2 p.Pro103Ser (c.307C>T) pathogenic?

GCM2 p.Pro103Ser (c.307C>T) is classified Uncertain significance in GCM2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-07-15). AlphaMissense: likely pathogenic (0.9969); Absent from gnomAD v4.1; Associated with hyperparathyroidism 4.

What condition is associated with GCM2 p.Pro103Ser (c.307C>T)?

GCM2 p.Pro103Ser (c.307C>T) is associated with hyperparathyroidism 4, hypoparathyroidism, familial isolated, 2 (ClinVar).

How common is GCM2 p.Pro103Ser (c.307C>T) in the general population?

GCM2 p.Pro103Ser (c.307C>T) is absent from gnomAD v4.1 (gnomAD).

How is Familial isolated hyperparathyroidism inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GCM2 p.Pro103Ser (c.307C>T)?

AlphaMissense predicts likely pathogenic (score 0.9969) — an in-silico prediction, not a clinical call.

GCM2 p.Pro103Ser

c.307C>T · rs1561672362 · VCV591144

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9969 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperparathyroidism 4

Computational evidence

Protein change
AlphaMissense	0.9969	likely pathogenic · top 3% in GCM2
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -12.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.37	donor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,221 bp · p 0.00012 · regional, not allelic
Overall
CADD	31.0	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

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.Pro103Ser
Coding: c.307C>T
MANE Select: NM_004752
dbSNP: rs1561672362
Type: single nucleotide variant
Location: chr6:10877176 (GRCh38)
Gene constraint: LOEUF 1.205 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.78
Residue 103: a DNA-binding region

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

Disease context

hyperparathyroidism 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypoparathyroidism, familial isolated, 2

For Familial isolated hyperparathyroidism (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

GCM2 p.Arg47Leu Pathogenic ★★ same condition
GCM2 p.Arg67Cys Likely pathogenic ★★ same condition
GCM2 p.Tyr136Ter Pathogenic ★★ same condition
GCM2 p.Ala148Val Uncertain significance ★★ ⚠ same condition
GCM2 p.Ala180Pro Uncertain significance ★★ ⚠ same condition
GCM2 p.Ala355Thr Uncertain significance ★★ ⚠ same condition
GCM2 p.Ala451Val Uncertain significance ★★ ⚠ same condition
GCM2 p.Ala488Thr Uncertain significance ★★ ⚠ 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/gcm2-p-pro103ser (accessed [today's date]).

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