Is GPD2 p.Phe635Ser (c.1904T>C) pathogenic?

GPD2 p.Phe635Ser (c.1904T>C) is classified Pathogenic in GPD2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 1997-02-24). AlphaMissense: likely pathogenic (0.9527); Absent from gnomAD v4.1; Associated with type 2 diabetes mellitus.

What condition is associated with GPD2 p.Phe635Ser (c.1904T>C)?

GPD2 p.Phe635Ser (c.1904T>C) is associated with type 2 diabetes mellitus (ClinVar).

How common is GPD2 p.Phe635Ser (c.1904T>C) in the general population?

GPD2 p.Phe635Ser (c.1904T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GPD2 p.Phe635Ser (c.1904T>C)?

AlphaMissense predicts likely pathogenic (score 0.9527) — an in-silico prediction, not a clinical call.

GPD2 p.Phe635Ser

c.1904T>C · rs121918407 · VCV16081

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9527 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type 2 diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.9527	likely pathogenic ✓ concordant with ClinVar
REVEL	0.752	pathogenic-leaning
SaProt	LLR -16.29	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 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 104 kb · p 3.5e-05 · regional, not allelic
Overall
CADD	27.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GPD2
Protein: p.Phe635Ser
Coding: c.1904T>C
MANE Select: NM_000408
dbSNP: rs121918407
Type: single nucleotide variant
Location: chr2:156579109 (GRCh38)
Gene constraint: LOEUF 0.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.47
Residue 635: a UniProt-annotated variant site (found in patients with type 2 diabetes; uncertain significance); the ef-hand 1 domain

Full GPD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

type 2 diabetes mellitus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GPD2 p.Asn224Lys Uncertain significance ★★ ⚠ same condition
GPD2 p.Ile75Val Conflicting classifications of pathogenicity ★ ⚠ same condition
GPD2 p.Pro205Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
GPD2 p.Ile308Val Likely benign ★★ same type
GPD2 c.497+5G>A Uncertain significance ★ same type
GPD2 p.Ala233Pro Uncertain significance ★ ⚠ same type
GPD2 p.Ala305Thr Uncertain significance ★ ⚠ same type
GPD2 p.Ala499Thr Conflicting classifications of pathogenicity ★ ⚠ 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/gpd2-p-phe635ser (accessed [today's date]).

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