Is ISCU p.Ala4Pro (c.10G>C) pathogenic?

ISCU p.Ala4Pro (c.10G>C) is classified Conflicting classifications of pathogenicity in ISCU (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1448); Rare (popmax 0.611%, nfe); Associated with hereditary myopathy with lactic acidosis due to ISCU deficiency.

What condition is associated with ISCU p.Ala4Pro (c.10G>C)?

ISCU p.Ala4Pro (c.10G>C) is associated with hereditary myopathy with lactic acidosis due to ISCU deficiency (ClinVar).

How common is ISCU p.Ala4Pro (c.10G>C) in the general population?

ISCU p.Ala4Pro (c.10G>C) is rare (popmax 0.611%, nfe) (gnomAD).

What do computational predictors say about ISCU p.Ala4Pro (c.10G>C)?

AlphaMissense predicts likely benign (score 0.1448) — an in-silico prediction, not a clinical call.

ISCU p.Ala4Pro

Q: How is Hereditary myopathy with lactic acidosis due to ISCU deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.10G>C · rs558084375 · VCV214555

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1448 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.611%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary myopathy with lactic acidosis due to ISCU deficiency

Computational evidence

Protein change
AlphaMissense	0.1448	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -8.61	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 6.3	GERP -0.14, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 6,290 bp · p 0.16 · regional, not allelic
Overall
CADD	21.1	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 0.611% European (non-Finnish) · 6,838/1,119,014 alleles

Filtering AF 0.599% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.594%

Overall 0.528% 7,783/1,473,674 alleles · rare exomes 7,227/1,321,316 · genomes 556/152,358 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.611%	164
Finnishnot grpmax-eligible	0.502%	199
Remaining individualsnot grpmax-eligible	0.451%	222
South Asian	0.433%	231
Ashkenazi Jewishnot grpmax-eligible	0.211%	475
Amishnot grpmax-eligible	0.11%	912
Admixed American	0.0922%	1,084
African / African-American	0.0699%	1,431
Middle Eastern	0.0209%	4,776
East Asian	0.00281%	35,550

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.Ala4Pro
Coding: c.10G>C
MANE Select: NM_213595
dbSNP: rs558084375
Type: single nucleotide variant
Location: chr12:108562632 (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

hereditary myopathy with lactic acidosis due to ISCU deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary myopathy with lactic acidosis due to ISCU deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

ISCU p.Ala4= Likely benign ★ same residue
ISCU c.418+382G>C Pathogenic ★★ same condition
ISCU p.Ala105Gly Uncertain significance ★★ ⚠ same condition
ISCU c.419-162C>T Benign/Likely benign ★★ same condition
ISCU p.Ala12Val Benign ★★ same condition
ISCU p.Phe7Cys Benign/Likely benign ★★ same condition
ISCU p.Phe7Val Benign/Likely benign ★★ same condition
ISCU p.Gly50Glu Likely pathogenic ★ 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-ala4pro (accessed [today's date]).

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