Is ATOH1 p.Pro225Arg (c.674C>G) pathogenic?

ATOH1 p.Pro225Arg (c.674C>G) is classified Likely benign in ATOH1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-11-08). AlphaMissense: likely benign (0.125); Rare (popmax 0.128%, afr); Associated with ATOH1-related disorder.

What condition is associated with ATOH1 p.Pro225Arg (c.674C>G)?

ATOH1 p.Pro225Arg (c.674C>G) is associated with ATOH1-related disorder (ClinVar).

How common is ATOH1 p.Pro225Arg (c.674C>G) in the general population?

ATOH1 p.Pro225Arg (c.674C>G) is rare (popmax 0.128%, afr) (gnomAD).

What do computational predictors say about ATOH1 p.Pro225Arg (c.674C>G)?

AlphaMissense predicts likely benign (score 0.125) — an in-silico prediction, not a clinical call.

ATOH1 p.Pro225Arg

c.674C>G · rs142870406 · VCV3036732

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.125 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.128%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ATOH1-related disorder

Computational evidence

Protein change
AlphaMissense	0.125	likely benign
REVEL	0.332	indeterminate
SaProt	LLR -8.88	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 2.1	GERP 0.65, phastCons 0.007
Regional constraint	o/e 1.08	unconstrained · MANE · 1,061 bp · p 0.094 · regional, not allelic
Overall
CADD	15.67	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 0.128% African / African-American · 96/75,068 alleles

Filtering AF 0.107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0995%

Overall 0.00669% 108/1,613,606 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.128%	782
Remaining individualsnot grpmax-eligible	0.0112%	8,925
Admixed American	0.00667%	15,001
European (non-Finnish)	8.48e-05%	1,179,710

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: ATOH1
Protein: p.Pro225Arg
Coding: c.674C>G
MANE Select: NM_005172
dbSNP: rs142870406
Type: single nucleotide variant
Location: chr4:93829600 (GRCh38)
Gene constraint: LOEUF 0.767 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 60.06
Residue 225: the 'disordered' region

Full ATOH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ATOH1-related disorder

Similar variants

ATOH1 p.Pro225Gln Uncertain significance ★ ⚠ same residue
ATOH1 p.Pro148Ser Uncertain significance ⚠ same condition
ATOH1 p.Pro25Ala Uncertain significance ⚠ same condition
ATOH1 p.Ala282= Likely benign same condition
ATOH1 p.Glu45= Likely benign same condition
ATOH1 p.Pro50= Benign same condition
ATOH1 p.His344fs Pathogenic ★ same condition
ATOH1 p.Ala253fs Uncertain significance ★ 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/atoh1-p-pro225arg (accessed [today's date]).

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