Is CALCOCO2 p.His267Arg (c.800A>G) pathogenic?

CALCOCO2 p.His267Arg (c.800A>G) is classified Uncertain significance in CALCOCO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.0689); Ultra-rare (popmax 0.0434%, amr).

How common is CALCOCO2 p.His267Arg (c.800A>G) in the general population?

CALCOCO2 p.His267Arg (c.800A>G) is ultra-rare (popmax 0.0434%, amr) (gnomAD).

What do computational predictors say about CALCOCO2 p.His267Arg (c.800A>G)?

AlphaMissense predicts likely benign (score 0.0689) — an in-silico prediction, not a clinical call.

CALCOCO2 p.His267Arg

c.800A>G · rs765959609 · VCV2213831

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0689 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0434%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0689	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -4.33	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 2.9	GERP 0.94, phastCons 0.52
Regional constraint	o/e 0.82	unconstrained · MANE · 10 kb · p 0.0082 · regional, not allelic
Overall
CADD	15.04	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 0.0434% Admixed American · 26/59,974 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.00545% 88/1,613,436 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0434%	2,307
Remaining individualsnot grpmax-eligible	0.008%	12,494
South Asian	0.00659%	15,177
European (non-Finnish)	0.00424%	23,591
African / African-American	0.00134%	74,900

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: CALCOCO2
Protein: p.His267Arg
Coding: c.800A>G
MANE Select: NM_005831
dbSNP: rs765959609
Type: single nucleotide variant
Location: chr17:48852603 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 10 PDB

Full CALCOCO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALCOCO2 p.Ala175Val Uncertain significance ★ ⚠ same type
CALCOCO2 p.Ala323Asp Uncertain significance ★ ⚠ same type
CALCOCO2 p.Ala375Thr Uncertain significance ★ ⚠ same type
CALCOCO2 p.Arg117Gln Uncertain significance ★ ⚠ same type
CALCOCO2 p.Arg117Trp Uncertain significance ★ ⚠ same type
CALCOCO2 p.Arg126Cys Uncertain significance ★ ⚠ same type
CALCOCO2 p.Arg51His Uncertain significance ★ ⚠ same type
CALCOCO2 p.Arg67His 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/calcoco2-p-his267arg (accessed [today's date]).

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