Is IK p.Pro2Arg (c.5C>G) pathogenic?

IK p.Pro2Arg (c.5C>G) is classified Uncertain significance in IK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). AlphaMissense: ambiguous (0.5259); Very rare (popmax 0.00549%, sas).

How common is IK p.Pro2Arg (c.5C>G) in the general population?

IK p.Pro2Arg (c.5C>G) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about IK p.Pro2Arg (c.5C>G)?

AlphaMissense predicts ambiguous (score 0.5259) — an in-silico prediction, not a clinical call.

IK p.Pro2Arg

c.5C>G · rs1211272992 · VCV2261424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5259 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Computational evidence

Protein change
AlphaMissense	0.5259	ambiguous
REVEL	0.482	indeterminate
SaProt	LLR -7.17	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 3,809 bp · p 0.5 · regional, not allelic
Overall
CADD	29.5	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

Grpmax group 0.00549% South Asian · 5/91,086 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000372% 6/1,613,698 alleles · very rare exomes 5/1,461,676 · genomes 1/152,022 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,217
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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: IK
Protein: p.Pro2Arg
Coding: c.5C>G
MANE Select: NM_006083
dbSNP: rs1211272992
Type: single nucleotide variant
Location: chr5:140647913 (GRCh38)
Gene constraint: LOEUF 0.771 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.95 · 5 PDB
Residue 2: the 'disordered' region

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

Similar variants

IK p.Ala14Asp Uncertain significance ★ ⚠ same type
IK p.Ala446Ser Uncertain significance ★ same type
IK p.Arg214Cys Uncertain significance ★ ⚠ same type
IK p.Arg214His Uncertain significance ★ ⚠ same type
IK p.Arg334Gln Uncertain significance ★ ⚠ same type
IK p.Arg342Gln Uncertain significance ★ ⚠ same type
IK p.Arg342Trp Uncertain significance ★ ⚠ same type
IK p.Arg344Gln 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/ik-p-pro2arg (accessed [today's date]).

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