Is APTX p.Val61Ile (c.181G>A) pathogenic?

APTX p.Val61Ile (c.181G>A) is classified Uncertain significance in APTX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-25). Ultra-rare (popmax 0.04%, amr); Associated with Inborn genetic diseases.

What condition is associated with APTX p.Val61Ile (c.181G>A)?

APTX p.Val61Ile (c.181G>A) is associated with Inborn genetic diseases (ClinVar).

How common is APTX p.Val61Ile (c.181G>A) in the general population?

APTX p.Val61Ile (c.181G>A) is ultra-rare (popmax 0.04%, amr) (gnomAD).

APTX p.Val61Ile

c.181G>A · rs755448350 · VCV1256341

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.09	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.2	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 16 kb · p 0.77 · regional, not allelic
Overall
CADD	18.74	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% Admixed American · 24/59,992 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00192% 31/1,613,006 alleles · ultra-rare exomes 7/1,460,806 · genomes 24/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.04%	2,500
Middle Eastern	0.0191%	5,222
African / African-American	0.00668%	14,980
East Asian	0.00223%	44,898

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: APTX
Protein: p.Val61Ile
Coding: c.181G>A
MANE Select: NM_001195248
dbSNP: rs755448350
Type: single nucleotide variant
Location: chr9:32987846 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.52 · 11 PDB
Residue 61: the fha-like domain; the 'interactions with adprt/parp1 and ncl' region; a β-strand

Full APTX 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

APTX p.Val61= Uncertain significance ★ same residue
APTX p.Arg29His Uncertain significance ★★ same condition
APTX p.Arg3Gln Uncertain significance ★★ same condition
APTX p.Asn120Ser Uncertain significance ★★ same condition
APTX p.Glu103Lys Uncertain significance ★★ same condition
APTX p.Glu131Lys Uncertain significance ★★ same condition
APTX p.His320Leu Uncertain significance ★★ same condition
APTX p.Ile124Leu 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/aptx-p-val61ile (accessed [today's date]).

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