Is CALCOCO2 p.Asn421Ser (c.1262A>G) pathogenic?

CALCOCO2 p.Asn421Ser (c.1262A>G) is classified Uncertain significance in CALCOCO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-14). AlphaMissense: likely benign (0.0666); Very rare (popmax 0.00446%, eas).

How common is CALCOCO2 p.Asn421Ser (c.1262A>G) in the general population?

CALCOCO2 p.Asn421Ser (c.1262A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CALCOCO2 p.Asn421Ser (c.1262A>G)?

AlphaMissense predicts likely benign (score 0.0666) — an in-silico prediction, not a clinical call.

CALCOCO2 p.Asn421Ser

c.1262A>G · rs759882056 · VCV2590491

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0666	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -5.17	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 -0.72	GERP -4.4
Regional constraint	o/e 0.82	unconstrained · MANE · 10 kb · p 0.0082 · regional, not allelic
Overall
CADD	6.511	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 0.00446% East Asian · 2/44,888 alleles

Filtering AF 0.000954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00143% 23/1,613,768 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,444
South Asian	0.00329%	30,361
European (non-Finnish)	0.00153%	65,542

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.Asn421Ser
Coding: c.1262A>G
MANE Select: NM_005831
dbSNP: rs759882056
Type: single nucleotide variant
Location: chr17:48862926 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.16 · 10 PDB
Residue 421: the 'interaction with myo6' region; a β-strand

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-asn421ser (accessed [today's date]).

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