Is GCM2 p.Pro299= (c.897T>C) pathogenic?

GCM2 p.Pro299= (c.897T>C) is classified Benign/Likely benign in GCM2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-27). Common (popmax 5.16%, afr) — too common for a highly-penetrant pathogenic allele; Associated with familial hypoparathyroidism.

What condition is associated with GCM2 p.Pro299= (c.897T>C)?

GCM2 p.Pro299= (c.897T>C) is associated with familial hypoparathyroidism (ClinVar).

How is Familial isolated hypoparathyroidism inherited?

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

GCM2 p.Pro299=

Q: How common is GCM2 p.Pro299= (c.897T>C) in the general population?

GCM2 p.Pro299= (c.897T>C) is common (popmax 5.16%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.897T>C · rs73440491 · VCV355012

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 5.16%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

familial hypoparathyroidism

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.69	GERP -0.69
Overall
CADD	1.386	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.16% African / African-American · 3,869/75,048 alleles

Filtering AF 5.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.96%

Overall 0.731% 11,804/1,614,144 alleles · common exomes 9,112/1,461,814 · genomes 2,692/152,330 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.16%	19
Remaining individualsnot grpmax-eligible	0.866%	116
Admixed American	0.698%	143
Middle Eastern	0.66%	152
European (non-Finnish)	0.529%	189
South Asian	0.449%	223
Ashkenazi Jewishnot grpmax-eligible	0.385%	260
Finnishnot grpmax-eligible	0.272%	368
East Asian	0.00223%	44,876

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.Pro299=
Coding: c.897T>C
MANE Select: NM_004752
dbSNP: rs73440491
Type: single nucleotide variant
Location: chr6:10874619 (GRCh38)
Gene constraint: LOEUF 1.205 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.78
Residue 299: 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

familial hypoparathyroidism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial isolated hypoparathyroidism (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: All ages

Similar variants

GCM2 c.90+2T>G Likely pathogenic ★★ same condition
GCM2 p.Tyr136Ter Pathogenic ★★ same condition
GCM2 c.*217T>A Uncertain significance ★★ same condition
GCM2 p.Ala355Thr Uncertain significance ★★ ⚠ same condition
GCM2 p.Arg143Gln Uncertain significance ★★ ⚠ same condition
GCM2 p.Arg39Gln Uncertain significance ★★ ⚠ same condition
GCM2 p.Arg455Gln Uncertain significance ★★ ⚠ same condition
GCM2 p.Asn502His 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-pro299 (accessed [today's date]).

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