Is CCDC116 p.Cys519Tyr (c.1556G>A) pathogenic?

CCDC116 p.Cys519Tyr (c.1556G>A) is classified Uncertain significance in CCDC116 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-14). AlphaMissense: likely benign (0.0706); Ultra-rare (popmax 0.0557%, eas).

How common is CCDC116 p.Cys519Tyr (c.1556G>A) in the general population?

CCDC116 p.Cys519Tyr (c.1556G>A) is ultra-rare (popmax 0.0557%, eas) (gnomAD).

What do computational predictors say about CCDC116 p.Cys519Tyr (c.1556G>A)?

AlphaMissense predicts likely benign (score 0.0706) — an in-silico prediction, not a clinical call.

CCDC116 p.Cys519Tyr

c.1556G>A · rs530867184 · VCV2459102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0706 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0557%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0706	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -7.29	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 -0.54	GERP -2.7
Regional constraint	o/e 0.98	unconstrained · MANE · 3,885 bp · p 0.65 · regional, not allelic
Overall
CADD	0.861	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 0.0557% East Asian · 25/44,858 alleles

Filtering AF 0.0387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00192% 31/1,612,586 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0557%	1,794
Remaining individualsnot grpmax-eligible	0.0048%	20,825
Admixed American	0.00167%	60,024
African / African-American	0.00133%	75,002
European (non-Finnish)	8.47e-05%	1,179,966

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: CCDC116
Protein: p.Cys519Tyr
Coding: c.1556G>A
MANE Select: NM_152612
dbSNP: rs530867184
Type: single nucleotide variant
Location: chr22:21636784 (GRCh38)
Gene constraint: LOEUF 1.158 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.59
Residue 519: the 'disordered' region

Full CCDC116 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC116 c.73-8C>T Benign ★★ same type
CCDC116 p.Arg174= Benign ★★ same type
CCDC116 p.Asn302= Benign ★★ same type
CCDC116 p.Lys412Arg Benign ★★ same type
CCDC116 p.Pro293Leu Benign ★★ same type
CCDC116 p.Thr569= Benign ★★ same type
CCDC116 p.Val252Met Benign ★★ same type
CCDC116 p.Ala12Asp 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/ccdc116-p-cys519tyr (accessed [today's date]).

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