Is STEAP3 p.Arg217Ser (c.649C>A) pathogenic?

STEAP3 p.Arg217Ser (c.649C>A) is classified Uncertain significance in STEAP3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.2421); Very rare (popmax 0.00223%, eas).

How common is STEAP3 p.Arg217Ser (c.649C>A) in the general population?

STEAP3 p.Arg217Ser (c.649C>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about STEAP3 p.Arg217Ser (c.649C>A)?

AlphaMissense predicts likely benign (score 0.2421) — an in-silico prediction, not a clinical call.

STEAP3 p.Arg217Ser

c.649C>A · rs748187004 · VCV2896855

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2421 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2421	likely benign
REVEL	0.214	benign-leaning
SaProt	LLR -9.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.7	GERP 0.84, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 32 kb · p 0.55 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R207S vs ClinVar R217S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,864 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000558% 9/1,611,586 alleles · very rare exomes 9/1,459,262 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,415
East Asiangrpmax	0.00223%	44,864
European (non-Finnish)	0.00017%	589,964

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg217Ser
Coding: c.649C>A
MANE Select: NM_182915
dbSNP: rs748187004
Type: single nucleotide variant
Location: chr2:119247805 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.24 · 2 PDB

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

Similar variants

STEAP3 p.Arg217Cys Uncertain significance ★ ⚠ same residue
STEAP3 p.Arg217His Uncertain significance ★ ⚠ same residue
STEAP3 p.Ala490Thr 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
STEAP3 p.Gln87Arg Uncertain significance ★★ ⚠ same type
STEAP3 p.Glu141Lys 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-arg217ser (accessed [today's date]).

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