Is SLC10A2 p.Trp186Ter (c.557G>A) pathogenic?

SLC10A2 p.Trp186Ter (c.557G>A) is classified Uncertain significance in SLC10A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-10). Ultra-rare (popmax 0.035%, amr); Associated with SLC10A2-related disorder.

What condition is associated with SLC10A2 p.Trp186Ter (c.557G>A)?

SLC10A2 p.Trp186Ter (c.557G>A) is associated with SLC10A2-related disorder (ClinVar).

How common is SLC10A2 p.Trp186Ter (c.557G>A) in the general population?

SLC10A2 p.Trp186Ter (c.557G>A) is ultra-rare (popmax 0.035%, amr) (gnomAD).

SLC10A2 p.Trp186Ter

c.557G>A · rs867693048 · VCV2636692

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Conditions

SLC10A2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 6
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.35	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Overall
CADD	49.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.035% Admixed American · 21/59,982 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00137% 22/1,611,430 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,856
South Asian	0.0011%	91,040

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: SLC10A2
Protein: p.Trp186Ter
Coding: c.557G>A
MANE Select: NM_000452
dbSNP: rs867693048
Type: single nucleotide variant
Location: chr13:103052648 (GRCh38)
Gene constraint: LOEUF 1.464 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.88

Full SLC10A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SLC10A2-related disorder

Similar variants

SLC10A2 p.Ala111Val Uncertain significance ★★ ⚠ same condition
SLC10A2 p.Arg246Thr Uncertain significance ★★ same condition
SLC10A2 p.Asp124His Uncertain significance ★★ ⚠ same condition
SLC10A2 p.Val53Met Uncertain significance ★★ ⚠ same condition
SLC10A2 c.378-1G>A Likely pathogenic ★ same condition
SLC10A2 p.Leu207Arg Uncertain significance ★ ⚠ same condition
SLC10A2 p.Trp186fs Conflicting classifications of pathogenicity ★ same residue
SLC10A2 c.919+316G>C Uncertain significance 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/slc10a2-p-trp186ter (accessed [today's date]).

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