Is ATAD3A p.Phe489Val (c.1465T>G) pathogenic?

ATAD3A p.Phe489Val (c.1465T>G) is classified Uncertain significance in ATAD3A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: ambiguous (0.4371); Absent from gnomAD v4.1; Associated with Harel-Yoon syndrome.

What condition is associated with ATAD3A p.Phe489Val (c.1465T>G)?

ATAD3A p.Phe489Val (c.1465T>G) is associated with Harel-Yoon syndrome (ClinVar).

How common is ATAD3A p.Phe489Val (c.1465T>G) in the general population?

ATAD3A p.Phe489Val (c.1465T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ATAD3A p.Phe489Val (c.1465T>G)?

AlphaMissense predicts ambiguous (score 0.4371) — an in-silico prediction, not a clinical call.

ATAD3A p.Phe489Val

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.1465T>G · VCV3358965

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4371 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Harel-Yoon syndrome

Computational evidence

Protein change
AlphaMissense	0.4371	ambiguous
REVEL	0.709	pathogenic-leaning
Splicing
SpliceAI	Δ0.55	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 9,713 bp · p 0.11 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F537V vs ClinVar F489V) — 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.Phe489Val
Coding: c.1465T>G
MANE Select: NM_001170535
Type: single nucleotide variant
Location: chr1:1527822 (GRCh38)
Gene constraint: LOEUF 0.861 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35
Residue 489: 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.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
ATAD3A p.Leu437Gln 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-phe489val (accessed [today's date]).

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