Is SH3PXD2B p.Pro765Ala (c.2293C>G) pathogenic?

SH3PXD2B p.Pro765Ala (c.2293C>G) is classified Uncertain significance in SH3PXD2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.1903); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with SH3PXD2B p.Pro765Ala (c.2293C>G)?

SH3PXD2B p.Pro765Ala (c.2293C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SH3PXD2B p.Pro765Ala (c.2293C>G) in the general population?

SH3PXD2B p.Pro765Ala (c.2293C>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about SH3PXD2B p.Pro765Ala (c.2293C>G)?

AlphaMissense predicts likely benign (score 0.1903) — an in-silico prediction, not a clinical call.

SH3PXD2B p.Pro765Ala

c.2293C>G · VCV4630810

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1903	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -8.90	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,357 bp · p 0.88 · regional, not allelic
Overall
CADD	21.4	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 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000124% 2/1,614,056 alleles · very rare exomes 1/1,461,842 · genomes 1/152,214 · 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: SH3PXD2B
Protein: p.Pro765Ala
Coding: c.2293C>G
MANE Select: NM_001017995
Type: single nucleotide variant
Location: chr5:172338812 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 56.95
Residue 765: the 'disordered' region

Full SH3PXD2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SH3PXD2B p.Arg43Trp Likely pathogenic ★★ same condition
SH3PXD2B p.Ala431Val Uncertain significance ★★ ⚠ same condition
SH3PXD2B p.Arg244Lys Uncertain significance ★★ ⚠ same condition
SH3PXD2B p.Arg305Trp Uncertain significance ★★ ⚠ same condition
SH3PXD2B p.Arg539Gln Uncertain significance ★★ ⚠ same condition
SH3PXD2B p.Arg541Gln Uncertain significance ★★ ⚠ same condition
SH3PXD2B p.Arg541Trp Uncertain significance ★★ ⚠ same condition
SH3PXD2B p.Arg550Trp Uncertain significance ★★ ⚠ same condition

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/sh3pxd2b-p-pro765ala (accessed [today's date]).

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