Is SRPX2 p.Pro181Arg (c.542C>G) pathogenic?

SRPX2 p.Pro181Arg (c.542C>G) is classified Uncertain significance in SRPX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-26). AlphaMissense: likely pathogenic (0.6983); Ultra-rare (popmax 0.0409%, sas).

How common is SRPX2 p.Pro181Arg (c.542C>G) in the general population?

SRPX2 p.Pro181Arg (c.542C>G) is ultra-rare (popmax 0.0409%, sas) (gnomAD).

What do computational predictors say about SRPX2 p.Pro181Arg (c.542C>G)?

AlphaMissense predicts likely pathogenic (score 0.6983) — an in-silico prediction, not a clinical call.

SRPX2 p.Pro181Arg

c.542C>G · rs769478434 · VCV436870

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6983 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0409%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6983	likely pathogenic
REVEL	0.575	indeterminate
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.025 · regional, not allelic
Overall
CADD	26.1	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 0.0409% South Asian · 23/56,237 alleles

Filtering AF 0.0279% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0237%

Overall 0.00198% 24/1,209,567 alleles · ultra-rare exomes 24/1,096,187 · genomes 0/113,380 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0409%	2,445
Remaining individualsnot grpmax-eligible	0.0021%	47,580

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: SRPX2
Protein: p.Pro181Arg
Coding: c.542C>G
MANE Select: NM_014467
dbSNP: rs769478434
Type: single nucleotide variant
Location: chrX:100665252 (GRCh38)
Structure: AlphaFold pLDDT 86.75
Residue 181: the hyr domain

Full SRPX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SRPX2 c.961+1G>A Uncertain significance ★★ same type
SRPX2 p.Ala201Val Uncertain significance ★★ ⚠ same type
SRPX2 p.Arg185Cys Uncertain significance ★★ ⚠ same type
SRPX2 p.Arg185Leu Uncertain significance ★★ ⚠ same type
SRPX2 p.Arg413His Uncertain significance ★★ ⚠ same type
SRPX2 p.Arg430His Uncertain significance ★★ ⚠ same type
SRPX2 p.Arg54Gln Uncertain significance ★★ ⚠ same type
SRPX2 p.Asn327Lys 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/srpx2-p-pro181arg (accessed [today's date]).

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