Is CALCOCO2 p.Cys422Ser (c.1265G>C) pathogenic?

CALCOCO2 p.Cys422Ser (c.1265G>C) is classified Uncertain significance in CALCOCO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-24). AlphaMissense: likely pathogenic (0.9412); Absent from gnomAD v4.1.

How common is CALCOCO2 p.Cys422Ser (c.1265G>C) in the general population?

CALCOCO2 p.Cys422Ser (c.1265G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CALCOCO2 p.Cys422Ser (c.1265G>C)?

AlphaMissense predicts likely pathogenic (score 0.9412) — an in-silico prediction, not a clinical call.

CALCOCO2 p.Cys422Ser

c.1265G>C · VCV3994775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9412 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9412	likely pathogenic · top 4% in CALCOCO2
REVEL	0.191	benign-leaning
SaProt	LLR -12.72	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 10 kb · p 0.0082 · regional, not allelic
Overall
CADD	24.6	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: CALCOCO2
Protein: p.Cys422Ser
Coding: c.1265G>C
MANE Select: NM_005831
Type: single nucleotide variant
Location: chr17:48862929 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 10 PDB
Residue 422: the 'interaction with myo6' region; a binding site

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

Similar variants

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.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

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-cys422ser (accessed [today's date]).

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