Is PROKR2 p.Leu91Phe (c.271C>T) pathogenic?

PROKR2 p.Leu91Phe (c.271C>T) is classified Uncertain significance in PROKR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-01). AlphaMissense: ambiguous (0.4384); Very rare (popmax 0.00167%, amr).

How common is PROKR2 p.Leu91Phe (c.271C>T) in the general population?

PROKR2 p.Leu91Phe (c.271C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PROKR2 p.Leu91Phe (c.271C>T)?

AlphaMissense predicts ambiguous (score 0.4384) — an in-silico prediction, not a clinical call.

PROKR2 p.Leu91Phe

c.271C>T · rs765584064 · VCV2652195

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4384 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.4384	ambiguous
REVEL	0.364	indeterminate
SaProt	LLR -3.21	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 0.13, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic
Overall
CADD	26.0	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 0.00167% Admixed American · 1/60,036 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000958% 14/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,036
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	0.00102%	98,337

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.Leu91Phe
Coding: c.271C>T
MANE Select: NM_144773
dbSNP: rs765584064
Type: single nucleotide variant
Location: chr20:5314099 (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.Leu91= Conflicting classifications of pathogenicity ★ 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-leu91phe (accessed [today's date]).

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