Is PRORP p.Ala229Val (c.686C>T) pathogenic?

PRORP p.Ala229Val (c.686C>T) is classified Likely benign in PRORP (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-01). AlphaMissense: ambiguous (0.4015); Rare (popmax 0.782%, sas).

How common is PRORP p.Ala229Val (c.686C>T) in the general population?

PRORP p.Ala229Val (c.686C>T) is rare (popmax 0.782%, sas) (gnomAD).

What do computational predictors say about PRORP p.Ala229Val (c.686C>T)?

AlphaMissense predicts ambiguous (score 0.4015) — an in-silico prediction, not a clinical call.

PRORP p.Ala229Val

c.686C>T · rs45626032 · VCV3043006

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4015 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.782%, sas)

Computational evidence

Protein change
AlphaMissense	0.4015	ambiguous
REVEL	0.367	indeterminate
SaProt	LLR -7.79	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 150 kb · p 0.092 · regional, not allelic
Overall
CADD	24.6	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 0.782% South Asian · 712/91,084 alleles

Filtering AF 0.734% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.715%

Overall 0.18% 2,903/1,614,098 alleles · rare exomes 2,698/1,461,814 · genomes 205/152,284 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.782%	128
Middle Eastern	0.544%	184
Remaining individualsnot grpmax-eligible	0.184%	544
Ashkenazi Jewishnot grpmax-eligible	0.169%	592
European (non-Finnish)	0.155%	646
Admixed American	0.132%	760
Finnishnot grpmax-eligible	0.0765%	1,306
African / African-American	0.048%	2,084
East Asian	0.00669%	14,957

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: PRORP
Protein: p.Ala229Val
Coding: c.686C>T
MANE Select: NM_014672
dbSNP: rs45626032
Type: single nucleotide variant
Location: chr14:35123931 (GRCh38)
Gene constraint: LOEUF 0.999 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.19 · 5 PDB
Residue 229: an α-helix

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

Similar variants

PRORP p.Arg421Cys Uncertain significance ★★ ⚠ same type
PRORP p.Arg502Gln Uncertain significance ★★ ⚠ same type
PRORP p.Asn412Ser Uncertain significance ★★ ⚠ same type
PRORP p.Lys76= Likely benign ★★ same type
PRORP p.Ala434Asp Likely pathogenic ★ ⚠ same type
PRORP c.-1A>G Uncertain significance ★ same type
PRORP p.Ala104Val Uncertain significance ★ ⚠ same type
PRORP p.Ala158Thr 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/prorp-p-ala229val (accessed [today's date]).

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