Is ALAS2 p.Ala172Thr (c.514G>A) pathogenic?

ALAS2 p.Ala172Thr (c.514G>A) is classified Conflicting classifications of pathogenicity in ALAS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-04). AlphaMissense: likely benign (0.3045); Very rare (popmax 0.00134%, nfe); Associated with X-linked sideroblastic anemia 1.

What condition is associated with ALAS2 p.Ala172Thr (c.514G>A)?

ALAS2 p.Ala172Thr (c.514G>A) is associated with X-linked sideroblastic anemia 1 (ClinVar).

How common is ALAS2 p.Ala172Thr (c.514G>A) in the general population?

ALAS2 p.Ala172Thr (c.514G>A) is very rare (popmax 0.00134%, nfe) (gnomAD).

How is X-linked sideroblastic anemia inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALAS2 p.Ala172Thr (c.514G>A)?

AlphaMissense predicts likely benign (score 0.3045) — an in-silico prediction, not a clinical call.

ALAS2 p.Ala172Thr

c.514G>A · rs137852304 · VCV10473

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3045 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked sideroblastic anemia 1

Computational evidence

Protein change
AlphaMissense	0.3045	likely benign
REVEL	0.956	strongly pathogenic-leaning
SaProt	LLR -8.52	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	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	26.5	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 0.00134% European (non-Finnish) · 12/895,239 alleles

Filtering AF 0.000715% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000564%

Overall 0.00109% 12/1,097,883 alleles · very rare

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.Ala172Thr
Coding: c.514G>A
MANE Select: NM_000032
dbSNP: rs137852304
Type: single nucleotide variant
Location: chrX:55021176 (GRCh38)
Structure: AlphaFold pLDDT 82.76 · 27 PDB
Residue 172: an α-helix

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

Disease context

X-linked sideroblastic anemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked sideroblastic anemia (Orphanet):

Inheritance: X-linked recessive
Onset: All ages

Similar variants

ALAS2 p.Arg411Cys Pathogenic ★★ same condition
ALAS2 p.Arg452Cys Pathogenic ★★ same condition
ALAS2 p.Ala336Asp Uncertain significance ★★ ⚠ same condition
ALAS2 p.Cys471Arg Uncertain significance ★★ ⚠ same condition
ALAS2 c.824-15C>T Benign ★★ same condition
ALAS2 c.*124C>T Benign/Likely benign ★★ same condition
ALAS2 c.*56A>C Benign ★★ same condition
ALAS2 p.Ala542= Benign ★★ 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-ala172thr (accessed [today's date]).

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