Is GSDMD p.Pro341Ser (c.1021C>T) pathogenic?

GSDMD p.Pro341Ser (c.1021C>T) is classified Uncertain significance in GSDMD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.0915); Ultra-rare (popmax 0.0168%, mid).

How common is GSDMD p.Pro341Ser (c.1021C>T) in the general population?

GSDMD p.Pro341Ser (c.1021C>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about GSDMD p.Pro341Ser (c.1021C>T)?

AlphaMissense predicts likely benign (score 0.0915) — an in-silico prediction, not a clinical call.

GSDMD p.Pro341Ser

c.1021C>T · VCV4267451

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0915 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0915	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -7.76	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 -1.7	GERP 0.34
Regional constraint	o/e 1.02	unconstrained · MANE · 3,565 bp · p 0.69 · regional, not allelic
Overall
CADD	2.411	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 0.0168% Middle Eastern · 1/5,970 alleles

Filtering AF 0.00533% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00384%

Overall 0.000989% 14/1,415,196 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,970
African / African-American	0.0108%	9,265
Remaining individualsnot grpmax-eligible	0.00164%	60,882
South Asian	0.00115%	86,982
European (non-Finnish)	0.000259%	386,793

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: GSDMD
Protein: p.Pro341Ser
Coding: c.1021C>T
MANE Select: NM_024736
Type: single nucleotide variant
Location: chr8:143562233 (GRCh38)
Gene constraint: LOEUF 1.493 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 11 PDB
Residue 341: an α-helix

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

Similar variants

GSDMD p.Arg249His Benign ★★ same type
GSDMD p.Arg7= Likely benign ★★ same type
GSDMD p.Gln396Arg Benign ★★ same type
GSDMD p.Ser3= Benign ★★ same type
GSDMD p.Thr453Ala Benign ★★ same type
GSDMD p.Ala215Thr Uncertain significance ★ ⚠ same type
GSDMD p.Ala244Val Uncertain significance ★ ⚠ same type
GSDMD p.Ala255Thr 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/gsdmd-p-pro341ser (accessed [today's date]).

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