Is GGH p.Pro302Ser (c.904C>T) pathogenic?

GGH p.Pro302Ser (c.904C>T) is classified Uncertain significance in GGH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: ambiguous (0.3524); Very rare (popmax 0.00284%, afr).

How common is GGH p.Pro302Ser (c.904C>T) in the general population?

GGH p.Pro302Ser (c.904C>T) is very rare (popmax 0.00284%, afr) (gnomAD).

What do computational predictors say about GGH p.Pro302Ser (c.904C>T)?

AlphaMissense predicts ambiguous (score 0.3524) — an in-silico prediction, not a clinical call.

GGH p.Pro302Ser

c.904C>T · VCV4029604

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3524 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00284%, afr)

Computational evidence

Protein change
AlphaMissense	0.3524	ambiguous
REVEL	0.385	indeterminate
SaProt	LLR -12.85	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 0.75, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 23 kb · p 0.38 · regional, not allelic
Overall
CADD	24.0	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 0.00284% African / African-American · 2/70,536 alleles

Filtering AF 0.000471% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000176%

Overall 0.00132% 2/152,058 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: GGH
Protein: p.Pro302Ser
Coding: c.904C>T
MANE Select: NM_003878
Type: single nucleotide variant
Location: chr8:63015385 (GRCh38)
Gene constraint: LOEUF 1.488 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 94.01 · 1 PDB
Residue 302: the gamma-glutamyl hydrolase domain

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

Similar variants

GGH p.Ala261Ser Uncertain significance ★ ⚠ same type
GGH p.Ala295Thr Uncertain significance ★ ⚠ same type
GGH p.Ala58Val Uncertain significance ★ ⚠ same type
GGH p.Arg44Cys Uncertain significance ★ ⚠ same type
GGH p.Cys6Tyr Uncertain significance ★ ⚠ same type
GGH p.Glu278Gly Uncertain significance ★ ⚠ same type
GGH p.Gly5Ser Uncertain significance ★ ⚠ same type
GGH p.Gly5Val 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/ggh-p-pro302ser (accessed [today's date]).

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