Is CALCOCO2 p.Ala175Val (c.524C>T) pathogenic?

CALCOCO2 p.Ala175Val (c.524C>T) is classified Uncertain significance in CALCOCO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely benign (0.0847); Ultra-rare (popmax 0.0233%, amr).

How common is CALCOCO2 p.Ala175Val (c.524C>T) in the general population?

CALCOCO2 p.Ala175Val (c.524C>T) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about CALCOCO2 p.Ala175Val (c.524C>T)?

AlphaMissense predicts likely benign (score 0.0847) — an in-silico prediction, not a clinical call.

CALCOCO2 p.Ala175Val

c.524C>T · rs200324523 · VCV3136657

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0847 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0847	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 4,523 bp · p 0.48 · regional, not allelic
Overall
CADD	24.0	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 0.0233% Admixed American · 14/60,004 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.0013% 21/1,613,438 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,286
Remaining individualsnot grpmax-eligible	0.0032%	31,219
European (non-Finnish)	0.000424%	235,963

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.Ala175Val
Coding: c.524C>T
MANE Select: NM_005831
dbSNP: rs200324523
Type: single nucleotide variant
Location: chr17:48849358 (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.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-ala175val (accessed [today's date]).

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