Is STEAP3 p.Arg69Cys (c.205C>T) pathogenic?

STEAP3 p.Arg69Cys (c.205C>T) is classified Uncertain significance in STEAP3 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.3314); Ultra-rare (popmax 0.0156%, eas); Associated with severe congenital hypochromic anemia with ringed sideroblasts.

What condition is associated with STEAP3 p.Arg69Cys (c.205C>T)?

STEAP3 p.Arg69Cys (c.205C>T) is associated with severe congenital hypochromic anemia with ringed sideroblasts (ClinVar).

How common is STEAP3 p.Arg69Cys (c.205C>T) in the general population?

STEAP3 p.Arg69Cys (c.205C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about STEAP3 p.Arg69Cys (c.205C>T)?

AlphaMissense predicts likely benign (score 0.3314) — an in-silico prediction, not a clinical call.

STEAP3 p.Arg69Cys

Q: How is Severe congenital hypochromic anemia with ringed sideroblasts inherited?

Typically Unknown (Orphanet). A genetic counselor can assess individual risk for a family.

c.205C>T · VCV4082252

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3314 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

severe congenital hypochromic anemia with ringed sideroblasts

Computational evidence

Protein change
AlphaMissense	0.3314	likely benign
REVEL	0.587	indeterminate
SaProt	LLR -13.08	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -3.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 32 kb · p 0.55 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R59C vs ClinVar R69C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,832 alleles

Filtering AF 0.00727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00149% 24/1,612,726 alleles · ultra-rare exomes 18/1,460,390 · genomes 6/152,336 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,405
South Asian	0.00329%	30,355
African / African-American	0.00267%	37,519
Admixed American	0.00167%	60,028
Remaining individualsnot grpmax-eligible	0.0016%	62,428
European (non-Finnish)	0.000848%	117,884

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: STEAP3
Protein: p.Arg69Cys
Coding: c.205C>T
MANE Select: NM_182915
Type: single nucleotide variant
Location: chr2:119245671 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.24 · 2 PDB
Residue 59 UniProt numbering: a binding site; a β-strand

Full STEAP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

severe congenital hypochromic anemia with ringed sideroblasts — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe congenital hypochromic anemia with ringed sideroblasts (Orphanet):

Inheritance: Unknown
Onset: Infancy, Neonatal

Similar variants

STEAP3 p.Arg69His Uncertain significance ★ ⚠ same residue
STEAP3 c.1215+2771C>G Uncertain significance ★ same condition
STEAP3 p.Tyr249His Uncertain significance ★ ⚠ same condition
STEAP3 p.Ala490Thr Uncertain significance ★★ ⚠ same type
STEAP3 p.Arg217Ser Uncertain significance ★★ ⚠ same type
STEAP3 p.Arg293Trp Uncertain significance ★★ ⚠ same type
STEAP3 p.Arg336His Uncertain significance ★★ ⚠ same type
STEAP3 p.Arg466Cys 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/steap3-p-arg69cys (accessed [today's date]).

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