Is PROKR2 p.Val177Phe (c.529G>T) pathogenic?

PROKR2 p.Val177Phe (c.529G>T) is classified Uncertain significance in PROKR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.5849); Absent from gnomAD v4.1.

How common is PROKR2 p.Val177Phe (c.529G>T) in the general population?

PROKR2 p.Val177Phe (c.529G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROKR2 p.Val177Phe (c.529G>T)?

AlphaMissense predicts likely pathogenic (score 0.5849) — an in-silico prediction, not a clinical call.

PROKR2 p.Val177Phe

c.529G>T · VCV4745530

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5849 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5849	likely pathogenic
REVEL	0.77	pathogenic-leaning
SaProt	LLR -10.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PROKR2
Protein: p.Val177Phe
Coding: c.529G>T
MANE Select: NM_144773
Type: single nucleotide variant
Location: chr20:5302666 (GRCh38)
Gene constraint: LOEUF 1.492 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.50
Residue 177: a disulfide bond

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

Similar variants

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
PROKR2 p.Arg248Trp 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-val177phe (accessed [today's date]).

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