Is ISCA2 p.Val74Ala (c.221T>C) pathogenic?

ISCA2 p.Val74Ala (c.221T>C) is classified Uncertain significance in ISCA2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9529); Absent from gnomAD v4.1; Associated with multiple mitochondrial dysfunctions syndrome 4.

What condition is associated with ISCA2 p.Val74Ala (c.221T>C)?

ISCA2 p.Val74Ala (c.221T>C) is associated with multiple mitochondrial dysfunctions syndrome 4 (ClinVar).

How common is ISCA2 p.Val74Ala (c.221T>C) in the general population?

ISCA2 p.Val74Ala (c.221T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ISCA2 p.Val74Ala (c.221T>C)?

AlphaMissense predicts likely pathogenic (score 0.9529) — an in-silico prediction, not a clinical call.

ISCA2 p.Val74Ala

Q: How is Multiple mitochondrial dysfunctions syndrome type 4 inherited?

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

c.221T>C · rs2506119435 · VCV3234879

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9529 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple mitochondrial dysfunctions syndrome 4

Computational evidence

Protein change
AlphaMissense	0.9529	likely pathogenic
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -13.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 0.79, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,222 bp · p 0.44 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ISCA2
Protein: p.Val74Ala
Coding: c.221T>C
MANE Select: NM_194279
dbSNP: rs2506119435
Type: single nucleotide variant
Location: chr14:74494321 (GRCh38)
Gene constraint: LOEUF 1.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.98

Full ISCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

multiple mitochondrial dysfunctions syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple mitochondrial dysfunctions syndrome type 4 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

ISCA2 p.Val74Leu Uncertain significance ★ ⚠ same residue
ISCA2 p.Gly77Ser Pathogenic/Likely pathogenic ★★ same condition
ISCA2 p.Gln141Leu Uncertain significance ★★ ⚠ same condition
ISCA2 p.Leu52Phe Uncertain significance ★★ ⚠ same condition
ISCA2 c.71+3A>T Uncertain significance ★ same condition
ISCA2 p.Ala119Thr Conflicting classifications of pathogenicity ★ same condition
ISCA2 p.Arg105Gly Conflicting classifications of pathogenicity ★ ⚠ same condition
ISCA2 p.Arg105Ile 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/isca2-p-val74ala (accessed [today's date]).

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