Is ISCA2 p.Ala114Val (c.341C>T) pathogenic?

ISCA2 p.Ala114Val (c.341C>T) is classified Uncertain significance in ISCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-27). AlphaMissense: likely benign (0.1369); Very rare (popmax 0.00668%, eas); Associated with Inborn genetic diseases.

What condition is associated with ISCA2 p.Ala114Val (c.341C>T)?

ISCA2 p.Ala114Val (c.341C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ISCA2 p.Ala114Val (c.341C>T) in the general population?

ISCA2 p.Ala114Val (c.341C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about ISCA2 p.Ala114Val (c.341C>T)?

AlphaMissense predicts likely benign (score 0.1369) — an in-silico prediction, not a clinical call.

ISCA2 p.Ala114Val

c.341C>T · rs1254399904 · VCV2489640

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1369 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1369	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -7.54	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	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,222 bp · p 0.44 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00668% East Asian · 3/44,902 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000186% 3/1,614,022 alleles · very rare exomes 2/1,461,866 · genomes 1/152,156 · joint denominator

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.Ala114Val
Coding: c.341C>T
MANE Select: NM_194279
dbSNP: rs1254399904
Type: single nucleotide variant
Location: chr14:74494876 (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

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

Similar variants

ISCA2 p.Gln141Arg Uncertain significance ★★ ⚠ same condition
ISCA2 p.Gln141Leu Uncertain significance ★★ ⚠ same condition
ISCA2 p.Leu9Gln Uncertain significance ★★ ⚠ same condition
ISCA2 p.Lys85Arg Uncertain significance ★★ ⚠ same condition
ISCA2 p.Pro21Leu Uncertain significance ★★ ⚠ same condition
ISCA2 p.Glu47Ter Pathogenic ★ same condition
ISCA2 p.Ala38Thr Uncertain significance ★ ⚠ same condition
ISCA2 p.Ala45Thr 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-ala114val (accessed [today's date]).

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