Is ISCA1 p.Arg83Ser (c.249A>T) pathogenic?

ISCA1 p.Arg83Ser (c.249A>T) is classified Uncertain significance in ISCA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-08). AlphaMissense: likely pathogenic (0.7255); Absent from gnomAD v4.1.

How common is ISCA1 p.Arg83Ser (c.249A>T) in the general population?

ISCA1 p.Arg83Ser (c.249A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ISCA1 p.Arg83Ser (c.249A>T)?

AlphaMissense predicts likely pathogenic (score 0.7255) — an in-silico prediction, not a clinical call.

ISCA1 p.Arg83Ser

c.249A>T · rs2489621566 · VCV2003422

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7255 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7255	likely pathogenic
REVEL	0.22	benign-leaning
SaProt	LLR -13.39	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.2	GERP 2.4, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 16 kb · p 8.6e-05 · regional, not allelic
Overall
CADD	22.7	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

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: ISCA1
Protein: p.Arg83Ser
Coding: c.249A>T
MANE Select: NM_030940
dbSNP: rs2489621566
Type: single nucleotide variant
Location: chr9:86266184 (GRCh38)
Gene constraint: LOEUF 1.785 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.18

Full ISCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ISCA1 p.Arg83Lys Uncertain significance ★ ⚠ same residue
ISCA1 c.241+92G>A Benign ★★ same type
ISCA1 p.Asn116= Benign ★★ same type
ISCA1 p.Val111= Likely benign ★★ same type
ISCA1 p.Ala31Thr Uncertain significance ★ ⚠ same type
ISCA1 p.Ala8Ser Uncertain significance ★ ⚠ same type
ISCA1 p.Arg7Pro Uncertain significance ★ ⚠ same type
ISCA1 p.Asn113Ser Uncertain significance ★ ⚠ same type

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/isca1-p-arg83ser (accessed [today's date]).

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