Is CCDC80 p.Arg514Trp (c.1540C>T) pathogenic?

CCDC80 p.Arg514Trp (c.1540C>T) is classified Uncertain significance in CCDC80 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.0984); Ultra-rare (popmax 0.0164%, mid).

How common is CCDC80 p.Arg514Trp (c.1540C>T) in the general population?

CCDC80 p.Arg514Trp (c.1540C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CCDC80 p.Arg514Trp (c.1540C>T)?

AlphaMissense predicts likely benign (score 0.0984) — an in-silico prediction, not a clinical call.

CCDC80 p.Arg514Trp

c.1540C>T · VCV4221571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0984 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0984	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -8.28	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 1.6	GERP -2.7, phastCons 0.96
Regional constraint	o/e 1.01	unconstrained · MANE · 34 kb · p 0.85 · regional, not allelic
Overall
CADD	21.7	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00118% 19/1,613,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00333%	29,989
East Asian	0.00223%	44,876
African / African-American	0.00134%	74,828
European (non-Finnish)	0.00119%	84,287

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: CCDC80
Protein: p.Arg514Trp
Coding: c.1540C>T
MANE Select: NM_199511
Type: single nucleotide variant
Location: chr3:112638366 (GRCh38)
Gene constraint: LOEUF 0.749 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.51
Residue 514: the 'disordered' region

Full CCDC80 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC80 p.Ala805Val Benign ★★ ⚠ same type
CCDC80 p.His473Tyr Benign ★★ same type
CCDC80 p.Tyr163= Benign ★★ same type
CCDC80 p.Tyr938His Likely benign ★★ ⚠ same type
CCDC80 p.Ala101Val Uncertain significance ★ ⚠ same type
CCDC80 p.Ala110Pro Uncertain significance ★ ⚠ same type
CCDC80 p.Ala110Ser Uncertain significance ★ ⚠ same type
CCDC80 p.Ala125Pro 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/ccdc80-p-arg514trp (accessed [today's date]).

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