Is ALAS2 p.Ser573Phe (c.1718C>T) pathogenic?

ALAS2 p.Ser573Phe (c.1718C>T) is classified Benign/Likely benign in ALAS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-14). AlphaMissense: ambiguous (0.3786); Ultra-rare (popmax 0.0694%, nfe); Associated with X-linked sideroblastic anemia 1.

What condition is associated with ALAS2 p.Ser573Phe (c.1718C>T)?

ALAS2 p.Ser573Phe (c.1718C>T) is associated with X-linked sideroblastic anemia 1 (ClinVar).

How common is ALAS2 p.Ser573Phe (c.1718C>T) in the general population?

ALAS2 p.Ser573Phe (c.1718C>T) is ultra-rare (popmax 0.0694%, 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.Ser573Phe (c.1718C>T)?

AlphaMissense predicts ambiguous (score 0.3786) — an in-silico prediction, not a clinical call.

ALAS2 p.Ser573Phe

c.1718C>T · rs201799139 · VCV214091

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.3786 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0694%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

X-linked sideroblastic anemia 1

Computational evidence

Protein change
AlphaMissense	0.3786	ambiguous
REVEL	0.656	pathogenic-leaning
SaProt	LLR -6.86	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 5,683 bp · p 0.0045 · regional, not allelic
Overall
CADD	24.8	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 0.0694% European (non-Finnish) · 620/893,574 alleles

Filtering AF 0.0648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.063%

Overall 0.0536% 646/1,206,177 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0694%	1,441
Remaining individualsnot grpmax-eligible	0.0316%	3,167
African / African-American	0.0105%	9,487
South Asian	0.00896%	11,167

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.Ser573Phe
Coding: c.1718C>T
MANE Select: NM_000032
dbSNP: rs201799139
Type: single nucleotide variant
Location: chrX:55009226 (GRCh38)
Structure: AlphaFold pLDDT 82.76 · 27 PDB
Residue 573: 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-ser573phe (accessed [today's date]).

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