Is GSDME p.Pro374= (c.1122C>T) pathogenic?

GSDME p.Pro374= (c.1122C>T) is classified Conflicting classifications of pathogenicity in GSDME (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-07-22). Ultra-rare (popmax 0.0907%, nfe); Associated with autosomal dominant nonsyndromic hearing loss 5.

What condition is associated with GSDME p.Pro374= (c.1122C>T)?

GSDME p.Pro374= (c.1122C>T) is associated with autosomal dominant nonsyndromic hearing loss 5 (ClinVar).

How common is GSDME p.Pro374= (c.1122C>T) in the general population?

GSDME p.Pro374= (c.1122C>T) is ultra-rare (popmax 0.0907%, nfe) (gnomAD).

GSDME p.Pro374=

c.1122C>T · rs138980048 · VCV178332

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0907%, nfe)

Conditions

autosomal dominant nonsyndromic hearing loss 5

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 -6.9	GERP -5
Overall
CADD	0.278	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0907% European (non-Finnish) · 1,070/1,180,046 alleles

Filtering AF 0.0861% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0843%

Overall 0.0716% 1,155/1,614,072 alleles · ultra-rare exomes 1,094/1,461,880 · genomes 61/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0907%	1,103
Remaining individualsnot grpmax-eligible	0.0576%	1,736
Finnishnot grpmax-eligible	0.0562%	1,779
African / African-American	0.0133%	7,494
Admixed American	0.005%	20,001

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: GSDME
Protein: p.Pro374=
Coding: c.1122C>T
MANE Select: NM_001127453
dbSNP: rs138980048
Type: single nucleotide variant
Location: chr7:24706245 (GRCh38)
Gene constraint: LOEUF 1.142 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 4 PDB

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

Disease context

autosomal dominant nonsyndromic hearing loss 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GSDME p.Pro374Leu Uncertain significance ★ ⚠ same residue
GSDME p.Ala400Thr Uncertain significance ★★ ⚠ same condition
GSDME p.Arg119Lys Uncertain significance ★★ ⚠ same condition
GSDME p.Arg450His Uncertain significance ★★ ⚠ same condition
GSDME p.Asn152Lys Uncertain significance ★★ ⚠ same condition
GSDME p.Leu92Arg Uncertain significance ★★ ⚠ same condition
GSDME p.Lys83Glu Uncertain significance ★★ ⚠ same condition
GSDME p.Pro212Leu 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/gsdme-p-pro374 (accessed [today's date]).

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