Is CALCOCO2 p.Thr65Ala (c.193A>G) pathogenic?

CALCOCO2 p.Thr65Ala (c.193A>G) is classified Uncertain significance in CALCOCO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-21). AlphaMissense: ambiguous (0.4178); Very rare (popmax 0.00167%, amr).

How common is CALCOCO2 p.Thr65Ala (c.193A>G) in the general population?

CALCOCO2 p.Thr65Ala (c.193A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CALCOCO2 p.Thr65Ala (c.193A>G)?

AlphaMissense predicts ambiguous (score 0.4178) — an in-silico prediction, not a clinical call.

CALCOCO2 p.Thr65Ala

c.193A>G · rs2509709233 · VCV2295881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4178 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4178	ambiguous
REVEL	0.288	benign-leaning
SaProt	LLR -12.02	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
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 1.05	unconstrained · MANE · 4,523 bp · p 0.48 · regional, not allelic
Overall
CADD	29.8	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 0.00167% Admixed American · 1/59,870 alleles

Overall 0.000137% 2/1,455,372 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,870
Remaining individualsnot grpmax-eligible	0.00161%	62,262

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.Thr65Ala
Coding: c.193A>G
MANE Select: NM_005831
dbSNP: rs2509709233
Type: single nucleotide variant
Location: chr17:48848076 (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.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-thr65ala (accessed [today's date]).

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