Is GCM2 p.Pro280Ser (c.838C>T) pathogenic?

GCM2 p.Pro280Ser (c.838C>T) is classified Uncertain significance in GCM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-17). AlphaMissense: likely benign (0.0783); Very rare (popmax 0.00534%, afr); Associated with hyperparathyroidism 4.

What condition is associated with GCM2 p.Pro280Ser (c.838C>T)?

GCM2 p.Pro280Ser (c.838C>T) is associated with hyperparathyroidism 4, hypoparathyroidism, familial isolated, 2 (ClinVar).

How common is GCM2 p.Pro280Ser (c.838C>T) in the general population?

GCM2 p.Pro280Ser (c.838C>T) is very rare (popmax 0.00534%, afr) (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.Pro280Ser (c.838C>T)?

AlphaMissense predicts likely benign (score 0.0783) — an in-silico prediction, not a clinical call.

GCM2 p.Pro280Ser

c.838C>T · VCV3592964

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0783 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperparathyroidism 4

Computational evidence

Protein change
AlphaMissense	0.0783	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -5.64	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 1.2	GERP -0.24, phastCons 0.67
Regional constraint	o/e 0.83	unconstrained · MANE · 3,221 bp · p 0.00012 · regional, not allelic
Overall
CADD	15.13	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 0.00534% African / African-American · 4/74,916 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,614,002 alleles · very rare exomes 2/1,461,834 · genomes 2/152,168 · joint denominator

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: GCM2
Protein: p.Pro280Ser
Coding: c.838C>T
MANE Select: NM_004752
Type: single nucleotide variant
Location: chr6:10874678 (GRCh38)
Gene constraint: LOEUF 1.205 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.78
Residue 280: 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

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-pro280ser (accessed [today's date]).

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