Is ATAD3C p.Pro409His (c.1226C>A) pathogenic?

ATAD3C p.Pro409His (c.1226C>A) is classified Uncertain significance in ATAD3C (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-09). AlphaMissense: likely benign (0.0707); Ultra-rare (popmax 0.0358%, eas).

How common is ATAD3C p.Pro409His (c.1226C>A) in the general population?

ATAD3C p.Pro409His (c.1226C>A) is ultra-rare (popmax 0.0358%, eas) (gnomAD).

What do computational predictors say about ATAD3C p.Pro409His (c.1226C>A)?

AlphaMissense predicts likely benign (score 0.0707) — an in-silico prediction, not a clinical call.

ATAD3C p.Pro409His

c.1226C>A · rs760744951 · VCV2259710

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0707 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0358%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0707	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -7.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3	GERP -2.1
Regional constraint	o/e 1.08	unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic
Overall
CADD	8.19	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0358% East Asian · 16/44,746 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.0011% 16/1,454,466 alleles · ultra-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: ATAD3C
Protein: p.Pro409His
Coding: c.1226C>A
MANE Select: NM_001039211
dbSNP: rs760744951
Type: single nucleotide variant
Location: chr1:1468520 (GRCh38)
Gene constraint: LOEUF 1.15 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.72

Full ATAD3C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATAD3C p.Ala91Val Benign ★★ same type
ATAD3C p.His172Asn Likely benign ★★ same type
ATAD3C p.Ala101Thr Uncertain significance ★ ⚠ same type
ATAD3C p.Ala101Val Uncertain significance ★ ⚠ same type
ATAD3C p.Ala120Val Uncertain significance ★ ⚠ same type
ATAD3C p.Ala157Thr Uncertain significance ★ ⚠ same type
ATAD3C p.Ala224Thr Uncertain significance ★ same type
ATAD3C p.Ala240Thr 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/atad3c-p-pro409his (accessed [today's date]).

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