Is STEAP3 p.Arg186Ser (c.556C>A) pathogenic?

STEAP3 p.Arg186Ser (c.556C>A) is classified Uncertain significance in STEAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-07). AlphaMissense: likely benign (0.1548); Very rare (popmax 0.00272%, afr).

How common is STEAP3 p.Arg186Ser (c.556C>A) in the general population?

STEAP3 p.Arg186Ser (c.556C>A) is very rare (popmax 0.00272%, afr) (gnomAD).

What do computational predictors say about STEAP3 p.Arg186Ser (c.556C>A)?

AlphaMissense predicts likely benign (score 0.1548) — an in-silico prediction, not a clinical call.

STEAP3 p.Arg186Ser

c.556C>A · VCV3802332

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1548 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00272%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1548	likely benign
REVEL	0.037	moderately 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 1.8	GERP 1.5, phastCons 0.93
Regional constraint	o/e 0.98	unconstrained · MANE · 32 kb · p 0.55 · regional, not allelic
Overall
CADD	16.58	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 R176S vs ClinVar R186S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00272% African / African-American · 2/73,578 alleles

Filtering AF 0.000451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000169%

Overall 0.000193% 3/1,553,526 alleles · very rare exomes 1/1,401,226 · genomes 2/152,300 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00272%	36,789
European (non-Finnish)	8.67e-05%	1,153,379

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.Arg186Ser
Coding: c.556C>A
MANE Select: NM_182915
Type: single nucleotide variant
Location: chr2:119247712 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.24 · 2 PDB
Residue 176 UniProt numbering: an α-helix

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

Similar variants

STEAP3 p.Arg186Cys Uncertain significance ★ ⚠ same residue
STEAP3 p.Arg186His Uncertain significance ★ ⚠ same residue
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
STEAP3 p.Gln87Arg 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-arg186ser (accessed [today's date]).

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