Is ATAD3A p.Phe409Leu (c.1225T>C) pathogenic?

ATAD3A p.Phe409Leu (c.1225T>C) is classified Uncertain significance in ATAD3A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-26). AlphaMissense: likely pathogenic (0.9689); Very rare (popmax 0.000593%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ATAD3A p.Phe409Leu (c.1225T>C)?

ATAD3A p.Phe409Leu (c.1225T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ATAD3A p.Phe409Leu (c.1225T>C) in the general population?

ATAD3A p.Phe409Leu (c.1225T>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about ATAD3A p.Phe409Leu (c.1225T>C)?

AlphaMissense predicts likely pathogenic (score 0.9689) — an in-silico prediction, not a clinical call.

ATAD3A p.Phe409Leu

c.1225T>C · rs2524187594 · VCV3130680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9689 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9689	likely pathogenic · top 6% in ATAD3A
REVEL	0.908	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 9,713 bp · p 0.11 · regional, not allelic
Overall
CADD	24.6	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 F457L vs ClinVar F409L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,974 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,461,736 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.Phe409Leu
Coding: c.1225T>C
MANE Select: NM_001170535
dbSNP: rs2524187594
Type: single nucleotide variant
Location: chr1:1525250 (GRCh38)
Gene constraint: LOEUF 0.861 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.35
Residue 409: a UniProt-annotated variant site (in phrinl)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ATAD3A p.Phe409= Conflicting classifications of pathogenicity ★ same residue
ATAD3A p.Ala62Val Uncertain significance ★★ ⚠ same condition
ATAD3A p.Arg138Trp Uncertain significance ★★ same condition
ATAD3A p.Arg188Gln Uncertain significance ★★ ⚠ same condition
ATAD3A p.Arg208Cys Uncertain significance ★★ same condition
ATAD3A p.Arg212Cys Uncertain significance ★★ ⚠ same condition
ATAD3A p.Arg273Cys Uncertain significance ★★ ⚠ same condition
ATAD3A p.Arg327Gln 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-phe409leu (accessed [today's date]).

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