Is ATOH7 p.Ala59Val (c.176C>T) pathogenic?

ATOH7 p.Ala59Val (c.176C>T) is classified Uncertain significance in ATOH7 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-28). AlphaMissense: likely pathogenic (0.9951); Very rare (popmax 0.00142%, afr); Associated with foveal hypoplasia.

What condition is associated with ATOH7 p.Ala59Val (c.176C>T)?

ATOH7 p.Ala59Val (c.176C>T) is associated with foveal hypoplasia (ClinVar).

How common is ATOH7 p.Ala59Val (c.176C>T) in the general population?

ATOH7 p.Ala59Val (c.176C>T) is very rare (popmax 0.00142%, afr) (gnomAD).

What do computational predictors say about ATOH7 p.Ala59Val (c.176C>T)?

AlphaMissense predicts likely pathogenic (score 0.9951) — an in-silico prediction, not a clinical call.

ATOH7 p.Ala59Val

c.176C>T · rs754494518 · VCV812673

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00142%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

foveal hypoplasia

Computational evidence

Protein change
AlphaMissense	0.9951	likely pathogenic · top 7% in ATOH7
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -11.61	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 9.8	GERP 0.93, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 455 bp · p 0.39 · regional, not allelic
Overall
CADD	28.7	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 0.00142% African / African-American · 1/70,456 alleles

Filtering AF 0.000716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00056%

Overall 0.00105% 16/1,529,972 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00172%	58,066
African / African-Americangrpmax	0.00142%	70,456
European (non-Finnish)	0.00123%	81,047

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ATOH7
Protein: p.Ala59Val
Coding: c.176C>T
MANE Select: NM_145178
dbSNP: rs754494518
Type: single nucleotide variant
Location: chr10:68231502 (GRCh38)
Gene constraint: LOEUF 1.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.79
Residue 59: the bhlh domain; a UniProt-annotated variant site (found in patients with bilateral optic nerve hypoplasia; uncertain significance; abolishes heterodimerization with tcf3 e47 isoform; reduces dna-binding ability and abolishes transcriptional activation; no effect on nuclear localization)

Full ATOH7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

foveal hypoplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ATOH7 p.Ala59Thr Pathogenic same residue
ATOH7 p.Ala20Gly Uncertain significance ★★ ⚠ same type
ATOH7 p.Ala20Thr Uncertain significance ★★ ⚠ same type
ATOH7 p.Ala44Glu Uncertain significance ★★ ⚠ same type
ATOH7 p.Arg62Ser Uncertain significance ★★ ⚠ same type
ATOH7 p.Arg94Trp Uncertain significance ★★ same type
ATOH7 p.Asn46Ser Uncertain significance ★★ ⚠ same type
ATOH7 p.Asn57Ser 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/atoh7-p-ala59val (accessed [today's date]).

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