Is GSDMD p.Ser359Phe (c.1076C>T) pathogenic?

GSDMD p.Ser359Phe (c.1076C>T) is classified Uncertain significance in GSDMD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely benign (0.21); Very rare (popmax 0.00956%, eas).

How common is GSDMD p.Ser359Phe (c.1076C>T) in the general population?

GSDMD p.Ser359Phe (c.1076C>T) is very rare (popmax 0.00956%, eas) (gnomAD).

What do computational predictors say about GSDMD p.Ser359Phe (c.1076C>T)?

AlphaMissense predicts likely benign (score 0.21) — an in-silico prediction, not a clinical call.

GSDMD p.Ser359Phe

c.1076C>T · VCV3856050

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.21 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00956%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.21	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -10.77	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22	GERP -1.3
Regional constraint	o/e 1.02	unconstrained · MANE · 3,565 bp · p 0.69 · regional, not allelic
Overall
CADD	15.41	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00956% East Asian · 4/41,834 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0019%

Overall 0.000386% 6/1,556,342 alleles · very rare exomes 5/1,404,282 · genomes 1/152,060 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00956%	10,459
European (non-Finnish)	0.000174%	575,563

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.Ser359Phe
Coding: c.1076C>T
MANE Select: NM_024736
Type: single nucleotide variant
Location: chr8:143562288 (GRCh38)
Gene constraint: LOEUF 1.493 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.45 · 11 PDB
Residue 359: a β-strand

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-ser359phe (accessed [today's date]).

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