Is ATAD3A p.Ala334Pro (c.1000G>C) pathogenic?

ATAD3A p.Ala334Pro (c.1000G>C) is classified Uncertain significance in ATAD3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.9518); Absent from gnomAD v4.1; Associated with Harel-Yoon syndrome.

What condition is associated with ATAD3A p.Ala334Pro (c.1000G>C)?

ATAD3A p.Ala334Pro (c.1000G>C) is associated with Harel-Yoon syndrome (ClinVar).

How common is ATAD3A p.Ala334Pro (c.1000G>C) in the general population?

ATAD3A p.Ala334Pro (c.1000G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATAD3A p.Ala334Pro (c.1000G>C)?

AlphaMissense predicts likely pathogenic (score 0.9518) — an in-silico prediction, not a clinical call.

ATAD3A p.Ala334Pro

Q: How is Ocular anomalies-axonal neuropathy-developmental delay syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1000G>C · VCV4856322

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9518 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Harel-Yoon syndrome

Computational evidence

Protein change
AlphaMissense	0.9518	likely pathogenic · top 8% in ATAD3A
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -12.12	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 8.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 6,537 bp · p 0.3 · regional, not allelic
Overall
CADD	26.7	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A382P vs ClinVar A334P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ATAD3A
Protein: p.Ala334Pro
Coding: c.1000G>C
MANE Select: NM_001170535
Type: single nucleotide variant
Location: chr1:1523875 (GRCh38)
Gene constraint: LOEUF 0.861 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35
Residue 334: a UniProt-annotated variant site (in phrinl)

Full ATAD3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Harel-Yoon syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Ocular anomalies-axonal neuropathy-developmental delay syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

ATAD3A p.Ala334Ser Uncertain significance ★ ⚠ same residue
ATAD3A p.Arg528Gln Likely pathogenic ★★ ⚠ same condition
ATAD3A p.Arg528Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
ATAD3A c.283-3C>T Uncertain significance ★★ same condition
ATAD3A p.Arg138Trp Uncertain significance ★★ same condition
ATAD3A p.Arg273Ser Uncertain significance ★★ ⚠ same condition
ATAD3A p.Arg342His Uncertain significance ★★ ⚠ same condition
ATAD3A p.Glu545Lys 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/atad3a-p-ala334pro (accessed [today's date]).

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