Is CCDC50 p.Arg76His (c.227G>A) pathogenic?

CCDC50 p.Arg76His (c.227G>A) is classified Conflicting classifications of pathogenicity in CCDC50 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-10). AlphaMissense: likely benign (0.0815); Ultra-rare (popmax 0.0797%, nfe); Associated with autosomal dominant nonsyndromic hearing loss 44.

What condition is associated with CCDC50 p.Arg76His (c.227G>A)?

CCDC50 p.Arg76His (c.227G>A) is associated with autosomal dominant nonsyndromic hearing loss 44, hearing loss disorder (ClinVar).

How common is CCDC50 p.Arg76His (c.227G>A) in the general population?

CCDC50 p.Arg76His (c.227G>A) is ultra-rare (popmax 0.0797%, nfe) (gnomAD).

What do computational predictors say about CCDC50 p.Arg76His (c.227G>A)?

AlphaMissense predicts likely benign (score 0.0815) — an in-silico prediction, not a clinical call.

CCDC50 p.Arg76His

c.227G>A · rs138443787 · VCV1376607

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0815 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0797%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant nonsyndromic hearing loss 44

Computational evidence

Protein change
AlphaMissense	0.0815	likely benign
REVEL	0.633	indeterminate
SaProt	LLR -7.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP -0.01, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.39 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0797% European (non-Finnish) · 940/1,179,878 alleles

Filtering AF 0.0754% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0737%

Overall 0.0612% 987/1,613,870 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0797%	1,255
Remaining individualsnot grpmax-eligible	0.0432%	2,315
African / African-American	0.0173%	5,769
Middle Eastern	0.0165%	6,056
Admixed American	0.005%	19,994
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
Finnishnot grpmax-eligible	0.00156%	64,024
South Asian	0.0011%	91,072

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: CCDC50
Protein: p.Arg76His
Coding: c.227G>A
MANE Select: NM_178335
dbSNP: rs138443787
Type: single nucleotide variant
Location: chr3:191358112 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.90 · 1 PDB

Full CCDC50 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant nonsyndromic hearing loss 44 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hearing loss disorder

Similar variants

CCDC50 p.Arg76Cys Uncertain significance ★★ ⚠ same residue
CCDC50 p.Arg76= Benign ★★ same residue
CCDC50 p.Arg227Trp Uncertain significance ★★ same condition
CCDC50 c.1092+58C>T Benign ★★ same condition
CCDC50 c.1242+10G>A Benign ★★ same condition
CCDC50 c.50-4C>G Benign ★★ same condition
CCDC50 c.976+56A>G Benign ★★ same condition
CCDC50 c.976+6A>G Benign ★★ same condition

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/ccdc50-p-arg76his (accessed [today's date]).

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