Is FPGS p.Thr125Met (c.374C>T) pathogenic?

FPGS p.Thr125Met (c.374C>T) is classified Uncertain significance in FPGS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-05). AlphaMissense: ambiguous (0.4436); Very rare (popmax 0.000847%, nfe).

How common is FPGS p.Thr125Met (c.374C>T) in the general population?

FPGS p.Thr125Met (c.374C>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about FPGS p.Thr125Met (c.374C>T)?

AlphaMissense predicts ambiguous (score 0.4436) — an in-silico prediction, not a clinical call.

FPGS p.Thr125Met

c.374C>T · VCV3279706

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4436 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4436	ambiguous
REVEL	0.537	indeterminate
SaProt	LLR -11.16	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 4,384 bp · p 6.1e-09 · regional, not allelic
Overall
CADD	33.0	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 0.000847% European (non-Finnish) · 10/1,179,976 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000684% 10/1,461,828 alleles · very rare

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: FPGS
Protein: p.Thr125Met
Coding: c.374C>T
MANE Select: NM_004957
Type: single nucleotide variant
Location: chr9:127804688 (GRCh38)
Gene constraint: LOEUF 1.174 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.05

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

Similar variants

FPGS p.Ile22Val Benign ★★ same type
FPGS p.Ala10Ser Uncertain significance ★ ⚠ same type
FPGS p.Ala15Gly Uncertain significance ★ ⚠ same type
FPGS p.Ala19Gly Uncertain significance ★ ⚠ same type
FPGS p.Ala307Ser Uncertain significance ★ ⚠ same type
FPGS p.Ala395Thr Uncertain significance ★ ⚠ same type
FPGS p.Ala423Gly Uncertain significance ★ ⚠ same type
FPGS p.Ala451Thr 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/fpgs-p-thr125met (accessed [today's date]).

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