Is ALAS2 p.Arg368Gln (c.1103G>A) pathogenic?

ALAS2 p.Arg368Gln (c.1103G>A) is classified Conflicting classifications of pathogenicity in ALAS2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.0839); Rare (popmax 0.436%, mid).

How common is ALAS2 p.Arg368Gln (c.1103G>A) in the general population?

ALAS2 p.Arg368Gln (c.1103G>A) is rare (popmax 0.436%, mid) (gnomAD).

What do computational predictors say about ALAS2 p.Arg368Gln (c.1103G>A)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

ALAS2 p.Arg368Gln

c.1103G>A · rs371716491 · VCV383289

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.436%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -9.54	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 2.7	GERP -0.061, phastCons 0.99
Regional constraint	o/e 0.52	unconstrained · MANE · 8,973 bp · p 5.5e-15 · regional, not allelic
Overall
CADD	16.47	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 0.436% Middle Eastern · 19/4,355 alleles

Filtering AF 0.286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.238%

Overall 0.0158% 191/1,209,040 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.436%	229
European (non-Finnish)	0.0173%	5,774
Admixed American	0.011%	9,131
Remaining individualsnot grpmax-eligible	0.0105%	9,520
East Asian	0.00593%	16,856
African / African-American	0.00527%	18,958
Finnishnot grpmax-eligible	0.00215%	46,492
South Asian	0.00176%	56,712

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.Arg368Gln
Coding: c.1103G>A
MANE Select: NM_000032
dbSNP: rs371716491
Type: single nucleotide variant
Location: chrX:55015643 (GRCh38)
Structure: AlphaFold pLDDT 82.76 · 27 PDB

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

Similar variants

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
ALAS2 p.Ala336Asp 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-arg368gln (accessed [today's date]).

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