Is PROKR2 p.Ile56Ser (c.167T>G) pathogenic?

PROKR2 p.Ile56Ser (c.167T>G) is classified Uncertain significance in PROKR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely pathogenic (0.7071); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PROKR2 p.Ile56Ser (c.167T>G)?

PROKR2 p.Ile56Ser (c.167T>G) is associated with Inborn genetic diseases (ClinVar).

How common is PROKR2 p.Ile56Ser (c.167T>G) in the general population?

PROKR2 p.Ile56Ser (c.167T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PROKR2 p.Ile56Ser (c.167T>G)?

AlphaMissense predicts likely pathogenic (score 0.7071) — an in-silico prediction, not a clinical call.

PROKR2 p.Ile56Ser

c.167T>G · rs781268393 · VCV3219016

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7071 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7071	likely pathogenic
REVEL	0.536	indeterminate
SaProt	LLR -8.86	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.0097 · regional, not allelic
Overall
CADD	25.5	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

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.Ile56Ser
Coding: c.167T>G
MANE Select: NM_144773
dbSNP: rs781268393
Type: single nucleotide variant
Location: chr20:5314203 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROKR2 p.Ile56Thr Uncertain significance ★★ ⚠ same residue
PROKR2 p.Arg47Gln Uncertain significance ★★ ⚠ same condition
PROKR2 p.Glu377Lys Uncertain significance ★★ ⚠ same condition
PROKR2 p.Gly70Ser Uncertain significance ★★ same condition
PROKR2 p.Met179Ile Uncertain significance ★★ ⚠ same condition
PROKR2 p.Pro17His Uncertain significance ★★ ⚠ same condition
PROKR2 p.Ser130= Likely benign ★★ same condition
PROKR2 p.Ala170Val Uncertain significance ★ ⚠ same condition

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-ile56ser (accessed [today's date]).

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