Is ISCA2 p.Lys85Arg (c.254A>G) pathogenic?

ISCA2 p.Lys85Arg (c.254A>G) is classified Uncertain significance in ISCA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-19). AlphaMissense: likely benign (0.0871); Ultra-rare (popmax 0.068%, afr); Associated with Inborn genetic diseases.

What condition is associated with ISCA2 p.Lys85Arg (c.254A>G)?

ISCA2 p.Lys85Arg (c.254A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ISCA2 p.Lys85Arg (c.254A>G) in the general population?

ISCA2 p.Lys85Arg (c.254A>G) is ultra-rare (popmax 0.068%, afr) (gnomAD).

What do computational predictors say about ISCA2 p.Lys85Arg (c.254A>G)?

AlphaMissense predicts likely benign (score 0.0871) — an in-silico prediction, not a clinical call.

ISCA2 p.Lys85Arg

c.254A>G · rs148923908 · VCV1702668

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0871 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.068%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0871	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -9.37	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 1	GERP -0.69, phastCons 0.99
Regional constraint	o/e 0.94	unconstrained · MANE · 1,222 bp · p 0.44 · regional, not allelic
Overall
CADD	20.4	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 0.068% African / African-American · 51/75,012 alleles

Filtering AF 0.0531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00582% 94/1,614,086 alleles · ultra-rare exomes 68/1,461,804 · genomes 26/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.068%	1,471
East Asian	0.0178%	5,611
South Asian	0.00878%	11,386
Remaining individualsnot grpmax-eligible	0.008%	12,501
Admixed American	0.00333%	30,013
European (non-Finnish)	0.00161%	62,103
Finnishnot grpmax-eligible	0.00156%	64,038

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.Lys85Arg
Coding: c.254A>G
MANE Select: NM_194279
dbSNP: rs148923908
Type: single nucleotide variant
Location: chr14:74494354 (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

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ISCA2 p.Gln141Leu Uncertain significance ★★ ⚠ same condition
ISCA2 p.Leu9Gln Uncertain significance ★★ ⚠ same condition
ISCA2 p.Pro21Leu Uncertain significance ★★ ⚠ same condition
ISCA2 p.Glu47Ter Pathogenic ★ same condition
ISCA2 p.Ala114Val Uncertain significance ★ ⚠ 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-lys85arg (accessed [today's date]).

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