Is CIR1 p.Arg337Lys (c.1010G>A) pathogenic?

CIR1 p.Arg337Lys (c.1010G>A) is classified Uncertain significance in CIR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-08). AlphaMissense: likely benign (0.0706); Very rare (popmax 0.0022%, sas).

How common is CIR1 p.Arg337Lys (c.1010G>A) in the general population?

CIR1 p.Arg337Lys (c.1010G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CIR1 p.Arg337Lys (c.1010G>A)?

AlphaMissense predicts likely benign (score 0.0706) — an in-silico prediction, not a clinical call.

CIR1 p.Arg337Lys

c.1010G>A · VCV3493073

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0706	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -5.62	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 -2	GERP -3.8
Regional constraint	o/e 1.01	unconstrained · MANE · 30 kb · p 0.89 · regional, not allelic
Overall
CADD	5.919	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,082 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000558% 9/1,614,048 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,541
Finnishnot grpmax-eligible	0.00156%	64,016
European (non-Finnish)	0.000508%	196,672

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: CIR1
Protein: p.Arg337Lys
Coding: c.1010G>A
MANE Select: NM_004882
Type: single nucleotide variant
Location: chr2:174348840 (GRCh38)
Gene constraint: LOEUF 0.971 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.12 · 2 PDB
Residue 337: the 'disordered' region

Full CIR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CIR1 p.Arg183Gln Uncertain significance ★ ⚠ same type
CIR1 p.Arg391Gln Uncertain significance ★ ⚠ same type
CIR1 p.Arg406Gln Uncertain significance ★ ⚠ same type
CIR1 p.Arg406Trp Uncertain significance ★ ⚠ same type
CIR1 p.Asn193Asp Uncertain significance ★ ⚠ same type
CIR1 p.His352Tyr Uncertain significance ★ ⚠ same type
CIR1 p.Lys233Glu Uncertain significance ★ ⚠ same type
CIR1 p.Met434Thr 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/cir1-p-arg337lys (accessed [today's date]).

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