Is ISCU p.Phe7Val (c.19T>G) pathogenic?

ISCU p.Phe7Val (c.19T>G) is classified Benign/Likely benign in ISCU (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.1508); Common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hereditary myopathy with lactic acidosis due to ISCU deficiency.

What condition is associated with ISCU p.Phe7Val (c.19T>G)?

ISCU p.Phe7Val (c.19T>G) is associated with hereditary myopathy with lactic acidosis due to ISCU deficiency (ClinVar).

What do computational predictors say about ISCU p.Phe7Val (c.19T>G)?

AlphaMissense predicts likely benign (score 0.1508) — an in-silico prediction, not a clinical call.

ISCU p.Phe7Val

Q: How common is ISCU p.Phe7Val (c.19T>G) in the general population?

ISCU p.Phe7Val (c.19T>G) is common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.19T>G · rs10778647 · VCV768575

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1508 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 94.1%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary myopathy with lactic acidosis due to ISCU deficiency

Computational evidence

Protein change
AlphaMissense	0.1508	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -5.05	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 7	GERP 0.85, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 6,290 bp · p 0.16 · regional, not allelic
Overall
CADD	17.97	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 94.1% East Asian · 33,426/35,534 alleles

Filtering AF 93.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 92.9%

Overall 87.6% 1,286,091/1,468,804 alleles · common exomes 1,154,596/1,316,774 · genomes 131,495/152,030 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	94.1%	1
South Asian	92.5%	1
Ashkenazi Jewishnot grpmax-eligible	88.9%	1
Middle Eastern	88.6%	1
Remaining individualsnot grpmax-eligible	87.9%	1
European (non-Finnish)	87.4%	1
Amishnot grpmax-eligible	87.3%	1
Admixed American	86.2%	1
Finnishnot grpmax-eligible	84.6%	1
African / African-American	83.4%	1

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.Phe7Val
Coding: c.19T>G
MANE Select: NM_213595
dbSNP: rs10778647
Type: single nucleotide variant
Location: chr12:108562641 (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.Phe7Cys Benign/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.Gly50Glu Likely pathogenic ★ same condition
ISCU c.418+702T>C Uncertain significance ★ same condition
ISCU p.Ala126Thr 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-phe7val (accessed [today's date]).

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