Is ISCU p.Pro159Ala (c.475C>G) pathogenic?

ISCU p.Pro159Ala (c.475C>G) is classified Likely benign in ISCU (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.0655); Rare (popmax 0.273%, afr).

How common is ISCU p.Pro159Ala (c.475C>G) in the general population?

ISCU p.Pro159Ala (c.475C>G) is rare (popmax 0.273%, afr) (gnomAD).

What do computational predictors say about ISCU p.Pro159Ala (c.475C>G)?

AlphaMissense predicts likely benign (score 0.0655) — an in-silico prediction, not a clinical call.

ISCU p.Pro159Ala

c.475C>G · rs113036584 · VCV559225

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0655 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.273%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0655	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -12.54	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.46	GERP -5.8
Regional constraint	o/e 1.10	unconstrained · MANE · 6,290 bp · p 0.16 · regional, not allelic
Overall
CADD	12.59	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 0.273% African / African-American · 205/75,016 alleles

Filtering AF 0.243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.231%

Overall 0.0164% 264/1,613,280 alleles · rare exomes 157/1,461,006 · genomes 107/152,274 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.273%	366
Remaining individualsnot grpmax-eligible	0.0544%	1,838
Admixed American	0.02%	4,991
Middle Eastern	0.0165%	6,062
South Asian	0.0022%	45,381
European (non-Finnish)	0.000848%	117,971

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: ISCU
Protein: p.Pro159Ala
Coding: c.475C>G
MANE Select: NM_213595
dbSNP: rs113036584
Type: single nucleotide variant
Location: chr12:108568887 (GRCh38)
Gene constraint: LOEUF 1.542 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.17 · 18 PDB

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

Similar variants

ISCU c.418+382G>C Pathogenic ★★ same type
ISCU p.Ala105Gly Uncertain significance ★★ ⚠ same type
ISCU p.Ala13Val Uncertain significance ★★ ⚠ same type
ISCU p.Ala149Thr Uncertain significance ★★ ⚠ same type
ISCU p.Ala15Thr Uncertain significance ★★ ⚠ same type
ISCU p.Ala30Val Uncertain significance ★★ ⚠ same type
ISCU p.Ala6Val Uncertain significance ★★ ⚠ same type
ISCU p.Arg11Pro 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/iscu-p-pro159ala (accessed [today's date]).

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