Is SNX2 p.Ala135Pro (c.403G>C) pathogenic?

SNX2 p.Ala135Pro (c.403G>C) is classified Uncertain significance in SNX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.1498); Very rare (popmax 0.00807%, afr).

How common is SNX2 p.Ala135Pro (c.403G>C) in the general population?

SNX2 p.Ala135Pro (c.403G>C) is very rare (popmax 0.00807%, afr) (gnomAD).

What do computational predictors say about SNX2 p.Ala135Pro (c.403G>C)?

AlphaMissense predicts likely benign (score 0.1498) — an in-silico prediction, not a clinical call.

SNX2 p.Ala135Pro

c.403G>C · VCV4587559

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1498 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00807%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1498	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.041, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 27 kb · p 0.028 · regional, not allelic
Overall
CADD	22.7	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 0.00807% African / African-American · 6/74,352 alleles

Filtering AF 0.00349% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0024%

Overall 0.000376% 6/1,594,386 alleles · very rare exomes 3/1,442,346 · genomes 3/152,040 · joint denominator

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: SNX2
Protein: p.Ala135Pro
Coding: c.403G>C
MANE Select: NM_003100
Type: single nucleotide variant
Location: chr5:122801881 (GRCh38)
Gene constraint: LOEUF 0.521 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 76.87

Full SNX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SNX2 c.226+2T>C Uncertain significance ★ same type
SNX2 c.227-1G>A Uncertain significance ★ same type
SNX2 c.644-2A>G Uncertain significance ★ same type
SNX2 p.Ala2Val Uncertain significance ★ ⚠ same type
SNX2 p.Ala519Asp Uncertain significance ★ ⚠ same type
SNX2 p.Arg398His Uncertain significance ★ same type
SNX2 p.Arg472Ter Uncertain significance ★ same type
SNX2 p.Arg5Lys 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/snx2-p-ala135pro (accessed [today's date]).

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