Is ATAD3B p.Val259Phe (c.775G>T) pathogenic?

ATAD3B p.Val259Phe (c.775G>T) is classified Uncertain significance in ATAD3B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.127); Very rare (popmax 0.00334%, sas).

How common is ATAD3B p.Val259Phe (c.775G>T) in the general population?

ATAD3B p.Val259Phe (c.775G>T) is very rare (popmax 0.00334%, sas) (gnomAD).

What do computational predictors say about ATAD3B p.Val259Phe (c.775G>T)?

AlphaMissense predicts likely benign (score 0.127) — an in-silico prediction, not a clinical call.

ATAD3B p.Val259Phe

c.775G>T · VCV4161125

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.127 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.127	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -2.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.35	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.59	GERP -2.3
Regional constraint	o/e 1.14	unconstrained · MANE · 4,459 bp · p 0.018 · regional, not allelic
Overall
CADD	16.55	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 0.00334% South Asian · 3/89,850 alleles

Filtering AF 0.000887% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000446%

Overall 0.000207% 3/1,451,712 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: ATAD3B
Protein: p.Val259Phe
Coding: c.775G>T
MANE Select: NM_031921
Type: single nucleotide variant
Location: chr1:1485040 (GRCh38)
Gene constraint: LOEUF 1.152 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.69

Full ATAD3B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATAD3B p.Val259= Likely benign ★★ same residue
ATAD3B c.445-11C>G Benign ★★ same type
ATAD3B p.Ala71Ser Benign ★★ same type
ATAD3B p.Cys641= Benign ★★ same type
ATAD3B p.Phe274Tyr Benign/Likely benign ★★ same type
ATAD3B p.Pro639Ser Benign ★★ same type
ATAD3B c.1090-3C>T Uncertain significance ★ same type
ATAD3B c.325C>T 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/atad3b-p-val259phe (accessed [today's date]).

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