Is PYGM p.Ser344Phe (c.1031C>T) pathogenic?

PYGM p.Ser344Phe (c.1031C>T) is classified Uncertain significance in PYGM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-26). AlphaMissense: likely pathogenic (0.9907); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with PYGM p.Ser344Phe (c.1031C>T)?

PYGM p.Ser344Phe (c.1031C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PYGM p.Ser344Phe (c.1031C>T) in the general population?

PYGM p.Ser344Phe (c.1031C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PYGM p.Ser344Phe (c.1031C>T)?

AlphaMissense predicts likely pathogenic (score 0.9907) — an in-silico prediction, not a clinical call.

PYGM p.Ser344Phe

c.1031C>T · VCV3428752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9907	likely pathogenic
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -13.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.00017 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,868 alleles

Overall 0.000124% 2/1,613,550 alleles · very rare exomes 2/1,461,468 · genomes 0/152,082 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,868
European (non-Finnish)	8.48e-05%	1,179,802

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: PYGM
Protein: p.Ser344Phe
Coding: c.1031C>T
MANE Select: NM_005609
Type: single nucleotide variant
Location: chr11:64754314 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.41 · 1 PDB
Residue 344: a UniProt-annotated variant site (in gsd5); a turn

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PYGM p.Ser344= Likely benign ★ same residue
PYGM p.Ala448Thr Uncertain significance ★★ ⚠ same condition
PYGM p.Arg17His Uncertain significance ★★ ⚠ same condition
PYGM p.Arg310Cys Uncertain significance ★★ ⚠ same condition
PYGM p.Arg310His Uncertain significance ★★ ⚠ same condition
PYGM p.Arg428His Uncertain significance ★★ ⚠ same condition
PYGM p.Arg50Gln Uncertain significance ★★ same condition
PYGM p.Arg640Cys 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/pygm-p-ser344phe (accessed [today's date]).

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