Is PROKR2 p.Val131Ile (c.391G>A) pathogenic?

PROKR2 p.Val131Ile (c.391G>A) is classified Uncertain significance in PROKR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). AlphaMissense: likely benign (0.0853); Ultra-rare (popmax 0.0356%, eas).

How common is PROKR2 p.Val131Ile (c.391G>A) in the general population?

PROKR2 p.Val131Ile (c.391G>A) is ultra-rare (popmax 0.0356%, eas) (gnomAD).

What do computational predictors say about PROKR2 p.Val131Ile (c.391G>A)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

PROKR2 p.Val131Ile

c.391G>A · rs374021985 · VCV1895891

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -8.02	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 0.095	GERP 1.1, phastCons 0.002
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic
Overall
CADD	17.86	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 0.0356% East Asian · 16/44,892 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00465% 75/1,614,184 alleles · ultra-rare exomes 62/1,461,890 · genomes 13/152,294 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0356%	2,806
South Asian	0.0263%	3,795
Remaining individualsnot grpmax-eligible	0.0064%	15,626
African / African-American	0.00533%	18,758
European (non-Finnish)	0.00229%	43,705

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: PROKR2
Protein: p.Val131Ile
Coding: c.391G>A
MANE Select: NM_144773
dbSNP: rs374021985
Type: single nucleotide variant
Location: chr20:5313979 (GRCh38)
Gene constraint: LOEUF 1.492 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50

Full PROKR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PROKR2 p.Val131fs Pathogenic ★ same residue
PROKR2 p.Arg164Gln Likely pathogenic ★★ same type
PROKR2 p.Glu231Lys Likely pathogenic ★★ ⚠ same type
PROKR2 p.Tyr316Ter Likely pathogenic ★★ same type
PROKR2 p.Ala103Val Uncertain significance ★★ ⚠ same type
PROKR2 p.Ala129Thr Uncertain significance ★★ ⚠ same type
PROKR2 p.Ala156Thr Uncertain significance ★★ same type
PROKR2 p.Arg135Cys 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/prokr2-p-val131ile (accessed [today's date]).

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