Is GGH p.Pro161Ser (c.481C>T) pathogenic?

GGH p.Pro161Ser (c.481C>T) is classified Uncertain significance in GGH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-02). AlphaMissense: likely benign (0.1873); Ultra-rare (popmax 0.0158%, eas).

How common is GGH p.Pro161Ser (c.481C>T) in the general population?

GGH p.Pro161Ser (c.481C>T) is ultra-rare (popmax 0.0158%, eas) (gnomAD).

What do computational predictors say about GGH p.Pro161Ser (c.481C>T)?

AlphaMissense predicts likely benign (score 0.1873) — an in-silico prediction, not a clinical call.

GGH p.Pro161Ser

c.481C>T · rs781250938 · VCV2528599

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1873 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1873	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -11.02	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 5.1	GERP 0.91, 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 0.0158% East Asian · 7/44,188 alleles

Filtering AF 0.00736% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00521%

Overall 0.0005% 8/1,601,408 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0158%	6,313
Admixed American	0.00174%	57,396

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.Pro161Ser
Coding: c.481C>T
MANE Select: NM_003878
dbSNP: rs781250938
Type: single nucleotide variant
Location: chr8:63026176 (GRCh38)
Gene constraint: LOEUF 1.488 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 94.01 · 1 PDB
Residue 161: 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-pro161ser (accessed [today's date]).

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