Is ALAS2 p.Arg293Cys (c.877C>T) pathogenic?

ALAS2 p.Arg293Cys (c.877C>T) is classified Uncertain significance in ALAS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-11). AlphaMissense: likely benign (0.3317); Very rare (popmax 0.00413%, nfe).

How common is ALAS2 p.Arg293Cys (c.877C>T) in the general population?

ALAS2 p.Arg293Cys (c.877C>T) is very rare (popmax 0.00413%, nfe) (gnomAD).

What do computational predictors say about ALAS2 p.Arg293Cys (c.877C>T)?

AlphaMissense predicts likely benign (score 0.3317) — an in-silico prediction, not a clinical call.

ALAS2 p.Arg293Cys

c.877C>T · VCV4706840

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00413%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3317	likely benign
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -13.77	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 8,973 bp · p 5.5e-15 · regional, not allelic
Overall
CADD	27.1	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 0.00413% European (non-Finnish) · 37/895,395 alleles

Filtering AF 0.00305% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00266%

Overall 0.00382% 42/1,098,081 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00454%	22,041
Remaining individualsnot grpmax-eligible	0.0042%	23,821
European (non-Finnish)grpmax	0.00413%	24,200
East Asian	0.00296%	33,828
South Asian	0.00176%	56,962

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ALAS2
Protein: p.Arg293Cys
Coding: c.877C>T
MANE Select: NM_000032
Type: single nucleotide variant
Location: chrX:55017612 (GRCh38)
Structure: AlphaFold pLDDT 82.76 · 27 PDB
Residue 293: an α-helix

Full ALAS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALAS2 p.Arg293His Uncertain significance ★ ⚠ same residue
ALAS2 p.Arg170Cys Pathogenic/Likely pathogenic ★★ same type
ALAS2 p.Arg411Cys Pathogenic ★★ same type
ALAS2 p.Arg452Cys Pathogenic ★★ same type
ALAS2 p.Arg452His Pathogenic ★★ ⚠ same type
ALAS2 p.Arg452Ser Pathogenic ★★ ⚠ same type
ALAS2 c.1168+4A>C Uncertain significance ★★ same type
ALAS2 p.Ala282Thr 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/alas2-p-arg293cys (accessed [today's date]).

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