Is CALCOCO1 p.Ser562Phe (c.1685C>T) pathogenic?

CALCOCO1 p.Ser562Phe (c.1685C>T) is classified Uncertain significance in CALCOCO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0898); Very rare (popmax 0.00231%, sas).

How common is CALCOCO1 p.Ser562Phe (c.1685C>T) in the general population?

CALCOCO1 p.Ser562Phe (c.1685C>T) is very rare (popmax 0.00231%, sas) (gnomAD).

What do computational predictors say about CALCOCO1 p.Ser562Phe (c.1685C>T)?

AlphaMissense predicts likely benign (score 0.0898) — an in-silico prediction, not a clinical call.

CALCOCO1 p.Ser562Phe

c.1685C>T · VCV4647741

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0898 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00231%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0898	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -8.74	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 5.7	GERP 2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 13 kb · p 9.4e-07 · regional, not allelic
Overall
CADD	21.6	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 0.00231% South Asian · 2/86,698 alleles

Filtering AF 0.000695% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000544%

Overall 0.00107% 17/1,585,870 alleles · very rare exomes 15/1,433,682 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00231%	43,349
Finnishnot grpmax-eligible	0.00159%	63,070
European (non-Finnish)	0.0012%	83,433

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: CALCOCO1
Protein: p.Ser562Phe
Coding: c.1685C>T
MANE Select: NM_020898
Type: single nucleotide variant
Location: chr12:53713807 (GRCh38)
Gene constraint: LOEUF 0.629 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57
Residue 562: the 'c-terminal ad (ctnnb1 binding site); interaction with ccar1' region; the 'disordered' region

Full CALCOCO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALCOCO1 p.Gln112Lys Uncertain significance ★★ ⚠ same type
CALCOCO1 p.Ala303Thr Uncertain significance ★ ⚠ same type
CALCOCO1 p.Ala303Val Uncertain significance ★ ⚠ same type
CALCOCO1 p.Ala322Val Uncertain significance ★ ⚠ same type
CALCOCO1 p.Ala369Thr Uncertain significance ★ ⚠ same type
CALCOCO1 p.Ala395Thr Uncertain significance ★ ⚠ same type
CALCOCO1 p.Ala478Asp Uncertain significance ★ ⚠ same type
CALCOCO1 p.Ala519Thr 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/calcoco1-p-ser562phe (accessed [today's date]).

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