Is CALCOCO2 p.Arg117Trp (c.349C>T) pathogenic?

CALCOCO2 p.Arg117Trp (c.349C>T) is classified Uncertain significance in CALCOCO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-09). AlphaMissense: likely benign (0.3068); Ultra-rare (popmax 0.0521%, afr).

How common is CALCOCO2 p.Arg117Trp (c.349C>T) in the general population?

CALCOCO2 p.Arg117Trp (c.349C>T) is ultra-rare (popmax 0.0521%, afr) (gnomAD).

What do computational predictors say about CALCOCO2 p.Arg117Trp (c.349C>T)?

AlphaMissense predicts likely benign (score 0.3068) — an in-silico prediction, not a clinical call.

CALCOCO2 p.Arg117Trp

c.349C>T · rs375727042 · VCV2381544

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3068 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0521%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3068	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -11.48	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 4,523 bp · p 0.48 · regional, not allelic
Overall
CADD	29.2	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 0.0521% African / African-American · 39/74,866 alleles

Filtering AF 0.0392% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0346%

Overall 0.00372% 60/1,613,026 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0521%	1,920
Admixed American	0.015%	6,664
Remaining individualsnot grpmax-eligible	0.0112%	8,921
South Asian	0.0011%	91,066
European (non-Finnish)	0.000339%	294,796

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.Arg117Trp
Coding: c.349C>T
MANE Select: NM_005831
dbSNP: rs375727042
Type: single nucleotide variant
Location: chr17:48848387 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 10 PDB
Residue 117: a β-strand

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

Similar variants

CALCOCO2 p.Arg117Gln Uncertain significance ★ ⚠ same residue
CALCOCO2 p.His267Arg Uncertain significance ★★ ⚠ same type
CALCOCO2 p.Ala175Val Uncertain significance ★ ⚠ same type
CALCOCO2 p.Ala323Asp Uncertain significance ★ ⚠ same type
CALCOCO2 p.Ala375Thr 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-arg117trp (accessed [today's date]).

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