Is CCDC47 p.Arg454Cys (c.1360C>T) pathogenic?

CCDC47 p.Arg454Cys (c.1360C>T) is classified Uncertain significance in CCDC47 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely pathogenic (0.9912); Very rare (popmax 0.00223%, eas).

How common is CCDC47 p.Arg454Cys (c.1360C>T) in the general population?

CCDC47 p.Arg454Cys (c.1360C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CCDC47 p.Arg454Cys (c.1360C>T)?

AlphaMissense predicts likely pathogenic (score 0.9912) — an in-silico prediction, not a clinical call.

CCDC47 p.Arg454Cys

c.1360C>T · VCV4221263

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9912 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9912	likely pathogenic
REVEL	0.738	pathogenic-leaning
SaProt	LLR -14.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 19 kb · p 0.0049 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,882 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000682% 11/1,613,390 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
Finnishnot grpmax-eligible	0.00157%	63,592
European (non-Finnish)	0.000763%	131,110

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: CCDC47
Protein: p.Arg454Cys
Coding: c.1360C>T
MANE Select: NM_020198
Type: single nucleotide variant
Location: chr17:63751951 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.07 · 1 PDB
Residue 454: a UniProt-annotated variant site (in thns; loss-of-function variant affecting er calcium ion homeostasis in patient cells; no protein detected by western blot in patient cells); the 'disordered' region

Full CCDC47 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC47 p.Arg397Ter Pathogenic/Likely pathogenic ★★ same type
CCDC47 p.Asp75Tyr Uncertain significance ★★ ⚠ same type
CCDC47 p.Trp133Arg Uncertain significance ★★ ⚠ same type
CCDC47 c.1093+112G>A Benign ★★ same type
CCDC47 c.1094-3C>T Benign ★★ same type
CCDC47 c.735+15C>T Benign ★★ same type
CCDC47 p.Arg271Ter Likely pathogenic ★ same type
CCDC47 c.669+5G>T 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/ccdc47-p-arg454cys (accessed [today's date]).

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