Is PROK2 p.Leu71Pro (c.212T>C) pathogenic?

PROK2 p.Leu71Pro (c.212T>C) is classified Uncertain significance in PROK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-27). AlphaMissense: likely pathogenic (0.7148); Very rare (popmax 0.005%, amr).

How common is PROK2 p.Leu71Pro (c.212T>C) in the general population?

PROK2 p.Leu71Pro (c.212T>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about PROK2 p.Leu71Pro (c.212T>C)?

AlphaMissense predicts likely pathogenic (score 0.7148) — an in-silico prediction, not a clinical call.

PROK2 p.Leu71Pro

c.212T>C · rs1445383955 · VCV2977316

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7148 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7148	likely pathogenic
REVEL	0.588	indeterminate
SaProt	LLR -8.78	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 0.094, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 12 kb · p 0.61 · regional, not allelic
Overall
CADD	24.0	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 0.005% Admixed American · 3/60,030 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,614,134 alleles · very rare exomes 3/1,461,802 · genomes 0/152,332 · joint denominator

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: PROK2
Protein: p.Leu71Pro
Coding: c.212T>C
MANE Select: NM_001126128
dbSNP: rs1445383955
Type: single nucleotide variant
Location: chr3:71781477 (GRCh38)
Gene constraint: LOEUF 1.052 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 69.22

Full PROK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PROK2 p.Arg101Gln Uncertain significance ★★ ⚠ same type
PROK2 p.Arg101Trp Uncertain significance ★★ ⚠ same type
PROK2 p.Arg122Gln Uncertain significance ★★ ⚠ same type
PROK2 p.Asp66Asn Uncertain significance ★★ ⚠ same type
PROK2 p.Gly62Asp Uncertain significance ★★ ⚠ same type
PROK2 p.Val29Met Uncertain significance ★★ ⚠ same type
PROK2 c.285+14G>A Benign ★★ same type
PROK2 c.-35A>G Benign ★★ 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/prok2-p-leu71pro (accessed [today's date]).

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