Is ALAS2 p.Ala415Val (c.1244C>T) pathogenic?

ALAS2 p.Ala415Val (c.1244C>T) is classified Conflicting classifications of pathogenicity in ALAS2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-26). AlphaMissense: ambiguous (0.4871); Ultra-rare (popmax 0.0993%, afr); Associated with Inborn genetic diseases.

What condition is associated with ALAS2 p.Ala415Val (c.1244C>T)?

ALAS2 p.Ala415Val (c.1244C>T) is associated with Inborn genetic diseases, X-linked sideroblastic anemia 1 (ClinVar).

How common is ALAS2 p.Ala415Val (c.1244C>T) in the general population?

ALAS2 p.Ala415Val (c.1244C>T) is ultra-rare (popmax 0.0993%, afr) (gnomAD).

What do computational predictors say about ALAS2 p.Ala415Val (c.1244C>T)?

AlphaMissense predicts ambiguous (score 0.4871) — an in-silico prediction, not a clinical call.

ALAS2 p.Ala415Val

c.1244C>T · rs143328343 · VCV1702971

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4871 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0993%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4871	ambiguous
REVEL	0.832	moderately pathogenic-leaning
SaProt	LLR -11.27	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	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	29.5	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 0.0993% African / African-American · 57/57,393 alleles

Filtering AF 0.0786% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0713%

Overall 0.00546% 66/1,208,539 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0993%	1,007
Remaining individualsnot grpmax-eligible	0.0147%	6,788
Admixed American	0.00437%	22,888

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.Ala415Val
Coding: c.1244C>T
MANE Select: NM_000032
dbSNP: rs143328343
Type: single nucleotide variant
Location: chrX:55014940 (GRCh38)
Structure: AlphaFold pLDDT 82.76 · 27 PDB
Residue 415: an α-helix

Full ALAS2 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

Also linked: X-linked sideroblastic anemia 1

Similar variants

ALAS2 p.Arg411Cys Pathogenic ★★ same condition
ALAS2 p.Arg452Cys Pathogenic ★★ same condition
ALAS2 p.Ala336Asp Uncertain significance ★★ ⚠ same condition
ALAS2 p.Arg375His Uncertain significance ★★ ⚠ same condition
ALAS2 p.Arg479Trp Uncertain significance ★★ ⚠ same condition
ALAS2 p.Asp308Asn Uncertain significance ★★ ⚠ same condition
ALAS2 p.Cys471Arg Uncertain significance ★★ ⚠ same condition
ALAS2 p.Glu277Lys 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/alas2-p-ala415val (accessed [today's date]).

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