Is ISCU p.Arg11Trp (c.31C>T) pathogenic?

ISCU p.Arg11Trp (c.31C>T) is classified Uncertain significance in ISCU (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-05). AlphaMissense: likely pathogenic (0.6494); Very rare (popmax 0.00865%, eas); Associated with Inborn genetic diseases.

What condition is associated with ISCU p.Arg11Trp (c.31C>T)?

ISCU p.Arg11Trp (c.31C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ISCU p.Arg11Trp (c.31C>T) in the general population?

ISCU p.Arg11Trp (c.31C>T) is very rare (popmax 0.00865%, eas) (gnomAD).

What do computational predictors say about ISCU p.Arg11Trp (c.31C>T)?

AlphaMissense predicts likely pathogenic (score 0.6494) — an in-silico prediction, not a clinical call.

ISCU p.Arg11Trp

c.31C>T · rs761091987 · VCV1405830

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6494 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00865%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6494	likely pathogenic
REVEL	0.339	indeterminate
SaProt	LLR -8.48	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.37	GERP 0.53, phastCons 0.9
Regional constraint	o/e 1.10	unconstrained · MANE · 6,290 bp · p 0.16 · regional, not allelic
Overall
CADD	21.3	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 0.00865% East Asian · 3/34,690 alleles

Filtering AF 0.00229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.000549% 8/1,458,128 alleles · very rare exomes 7/1,305,974 · genomes 1/152,154 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00865%	11,563
South Asian	0.00137%	72,968
European (non-Finnish)	0.00036%	277,825

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.Arg11Trp
Coding: c.31C>T
MANE Select: NM_213595
dbSNP: rs761091987
Type: single nucleotide variant
Location: chr12:108562653 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ISCU p.Arg11Pro Uncertain significance ★★ ⚠ same residue
ISCU p.Ala13Val Uncertain significance ★★ ⚠ same condition
ISCU p.Ala15Thr Uncertain significance ★★ ⚠ same condition
ISCU p.Arg8Cys Uncertain significance ★★ ⚠ same condition
ISCU p.Lys166Asn Uncertain significance ★★ ⚠ same condition
ISCU p.Thr113Met Uncertain significance ★★ ⚠ same condition
ISCU p.Val49Met Uncertain significance ★★ ⚠ same condition
ISCU p.Ala148Ser 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/iscu-p-arg11trp (accessed [today's date]).

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