Is PROKR2 p.Pro12Arg (c.35C>G) pathogenic?

PROKR2 p.Pro12Arg (c.35C>G) is classified Likely benign in PROKR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-27). AlphaMissense: likely benign (0.0766); Rare (popmax 0.367%, afr).

How common is PROKR2 p.Pro12Arg (c.35C>G) in the general population?

PROKR2 p.Pro12Arg (c.35C>G) is rare (popmax 0.367%, afr) (gnomAD).

What do computational predictors say about PROKR2 p.Pro12Arg (c.35C>G)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

PROKR2 p.Pro12Arg

c.35C>G · rs147773715 · VCV696699

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.367%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -6.93	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 4.4	GERP 0.085, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic
Overall
CADD	15.42	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 0.367% African / African-American · 275/75,020 alleles

Filtering AF 0.331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.317%

Overall 0.0178% 287/1,614,114 alleles · rare exomes 144/1,461,850 · genomes 143/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.367%	273
Remaining individualsnot grpmax-eligible	0.0128%	7,814
Admixed American	0.00666%	15,005

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.Pro12Arg
Coding: c.35C>G
MANE Select: NM_144773
dbSNP: rs147773715
Type: single nucleotide variant
Location: chr20:5314335 (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.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-pro12arg (accessed [today's date]).

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