Is ATAD3A p.Arg273Ser (c.817C>A) pathogenic?

ATAD3A p.Arg273Ser (c.817C>A) is classified Uncertain significance in ATAD3A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-20). AlphaMissense: ambiguous (0.5311); Very rare (popmax 0.000678%, nfe); Associated with Harel-Yoon syndrome.

What condition is associated with ATAD3A p.Arg273Ser (c.817C>A)?

ATAD3A p.Arg273Ser (c.817C>A) is associated with Harel-Yoon syndrome (ClinVar).

How common is ATAD3A p.Arg273Ser (c.817C>A) in the general population?

ATAD3A p.Arg273Ser (c.817C>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about ATAD3A p.Arg273Ser (c.817C>A)?

AlphaMissense predicts ambiguous (score 0.5311) — an in-silico prediction, not a clinical call.

ATAD3A p.Arg273Ser

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.817C>A · rs574343682 · VCV587626

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5311 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

Harel-Yoon syndrome

Computational evidence

Protein change
AlphaMissense	0.5311	ambiguous
REVEL	0.734	pathogenic-leaning
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 6,537 bp · p 0.3 · regional, not allelic
Overall
CADD	27.6	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 R321S vs ClinVar R273S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,768 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000497% 8/1,611,126 alleles · very rare

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: ATAD3A
Protein: p.Arg273Ser
Coding: c.817C>A
MANE Select: NM_001170535
dbSNP: rs574343682
Type: single nucleotide variant
Location: chr1:1522810 (GRCh38)
Gene constraint: LOEUF 0.861 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35
Residue 273: 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.Arg273Cys Uncertain significance ★★ ⚠ same residue
ATAD3A p.Arg273His Uncertain significance ★ ⚠ same residue
ATAD3A p.Arg273Leu Uncertain significance ★ ⚠ same residue
ATAD3A p.Arg273Pro 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

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-arg273ser (accessed [today's date]).

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