Is AGXT p.Pro34Ser (c.100C>T) pathogenic?

AGXT p.Pro34Ser (c.100C>T) is classified Uncertain significance in AGXT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). AlphaMissense: likely benign (0.1231); Very rare (popmax 0.00276%, afr).

How common is AGXT p.Pro34Ser (c.100C>T) in the general population?

AGXT p.Pro34Ser (c.100C>T) is very rare (popmax 0.00276%, afr) (gnomAD).

What do computational predictors say about AGXT p.Pro34Ser (c.100C>T)?

AlphaMissense predicts likely benign (score 0.1231) — an in-silico prediction, not a clinical call.

AGXT p.Pro34Ser

c.100C>T · rs758388293 · VCV1951431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1231 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00276%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1231	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -2.5
Regional constraint	o/e 1.00	unconstrained · MANE · 9,952 bp · p 0.92 · regional, not allelic
Overall
CADD	0.009	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00276% African / African-American · 2/72,544 alleles

Filtering AF 0.000458% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000171%

Overall 0.000138% 2/1,452,996 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: AGXT
Protein: p.Pro34Ser
Coding: c.100C>T
MANE Select: NM_000030
dbSNP: rs758388293
Type: single nucleotide variant
Location: chr2:240868965 (GRCh38)
Gene constraint: LOEUF 1.251 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 98.30 · 17 PDB
Residue 34: an α-helix

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

Similar variants

AGXT c.358+1G>A Pathogenic ★★ same type
AGXT c.359-2A>G Likely pathogenic ★★ same type
AGXT c.423+1G>A Pathogenic/Likely pathogenic ★★ same type
AGXT c.524+2T>A Likely pathogenic ★★ same type
AGXT c.525-1G>A Pathogenic ★★ same type
AGXT c.525-2A>T Pathogenic/Likely pathogenic ★★ same type
AGXT c.595+1G>T Pathogenic ★★ same type
AGXT c.596-2A>G Pathogenic ★★ 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/agxt-p-pro34ser (accessed [today's date]).

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