Is DIABLO p.Ile59Val (c.175A>G) pathogenic?

DIABLO p.Ile59Val (c.175A>G) is classified Conflicting classifications of pathogenicity in DIABLO (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-12). AlphaMissense: likely benign (0.0667); Ultra-rare (popmax 0.0691%, eas).

How common is DIABLO p.Ile59Val (c.175A>G) in the general population?

DIABLO p.Ile59Val (c.175A>G) is ultra-rare (popmax 0.0691%, eas) (gnomAD).

What do computational predictors say about DIABLO p.Ile59Val (c.175A>G)?

AlphaMissense predicts likely benign (score 0.0667) — an in-silico prediction, not a clinical call.

DIABLO p.Ile59Val

c.175A>G · rs574777883 · VCV227299

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0667 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0691%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0667	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -6.10	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 0.23	GERP -0.97, phastCons 0.047
Regional constraint	o/e 1.10	unconstrained · MANE · 18 kb · p 0.08 · regional, not allelic
Overall
CADD	11.96	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0691% East Asian · 31/44,856 alleles

Filtering AF 0.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0435%

Overall 0.00471% 76/1,613,294 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0691%	1,447
Remaining individualsnot grpmax-eligible	0.0144%	6,944
South Asian	0.00549%	18,209
African / African-American	0.00401%	24,910
Admixed American	0.00334%	29,897
European (non-Finnish)	0.00212%	47,196
Finnishnot grpmax-eligible	0.00157%	63,890

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: DIABLO
Protein: p.Ile59Val
Coding: c.175A>G
MANE Select: NM_001371333
dbSNP: rs574777883
Type: single nucleotide variant
Location: chr12:122224520 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.53 · 16 PDB

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

Similar variants

DIABLO p.Arg10Cys Uncertain significance ★★ ⚠ same type
DIABLO p.Ser9Leu Uncertain significance ★★ ⚠ same type
DIABLO p.Tyr117His Uncertain significance ★★ ⚠ same type
DIABLO c.183+63G>A Benign ★★ same type
DIABLO c.184-70G>A Benign ★★ same type
DIABLO c.316-101T>C Likely benign ★★ same type
DIABLO c.316-258A>T Benign ★★ same type
DIABLO c.316-8A>G Benign/Likely benign ★★ 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/diablo-p-ile59val (accessed [today's date]).

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