Is ISCA2 p.Leu52Phe (c.154C>T) pathogenic?

ISCA2 p.Leu52Phe (c.154C>T) is classified Uncertain significance in ISCA2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-09-15). AlphaMissense: likely pathogenic (0.6139); Very rare (popmax 0.00889%, amr); Associated with multiple mitochondrial dysfunctions syndrome 4.

What condition is associated with ISCA2 p.Leu52Phe (c.154C>T)?

ISCA2 p.Leu52Phe (c.154C>T) is associated with multiple mitochondrial dysfunctions syndrome 4 (ClinVar).

How common is ISCA2 p.Leu52Phe (c.154C>T) in the general population?

ISCA2 p.Leu52Phe (c.154C>T) is very rare (popmax 0.00889%, amr) (gnomAD).

What do computational predictors say about ISCA2 p.Leu52Phe (c.154C>T)?

AlphaMissense predicts likely pathogenic (score 0.6139) — an in-silico prediction, not a clinical call.

ISCA2 p.Leu52Phe

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.154C>T · rs760723089 · VCV2740585

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6139 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00889%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple mitochondrial dysfunctions syndrome 4

Computational evidence

Protein change
AlphaMissense	0.6139	likely pathogenic
REVEL	0.284	benign-leaning
SaProt	LLR -12.05	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,222 bp · p 0.44 · regional, not allelic
Overall
CADD	29.4	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 0.00889% Admixed American · 5/56,240 alleles

Filtering AF 0.00343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00218%

Overall 0.000378% 6/1,587,242 alleles · very rare exomes 6/1,434,886 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00889%	11,248
Finnishnot grpmax-eligible	0.00167%	59,838

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: ISCA2
Protein: p.Leu52Phe
Coding: c.154C>T
MANE Select: NM_194279
dbSNP: rs760723089
Type: single nucleotide variant
Location: chr14:74494132 (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.Gly77Ser Pathogenic/Likely pathogenic ★★ same condition
ISCA2 p.Gln141Leu 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
ISCA2 p.Ser112Gly Uncertain significance ★ ⚠ same condition
ISCA2 p.Val121Leu Conflicting classifications of pathogenicity ★ 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-leu52phe (accessed [today's date]).

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