Is TSLP p.Ser92Trp (c.275C>G) pathogenic?

TSLP p.Ser92Trp (c.275C>G) is classified Uncertain significance in TSLP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-05). AlphaMissense: ambiguous (0.412); Very rare (popmax 0.00133%, afr).

How common is TSLP p.Ser92Trp (c.275C>G) in the general population?

TSLP p.Ser92Trp (c.275C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TSLP p.Ser92Trp (c.275C>G)?

AlphaMissense predicts ambiguous (score 0.412) — an in-silico prediction, not a clinical call.

TSLP p.Ser92Trp

c.275C>G · rs1267224802 · VCV2253341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.412 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.412	ambiguous
REVEL	0.223	benign-leaning
SaProt	LLR -11.52	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 2.1, phastCons 0.009
Regional constraint	o/e 1.17	unconstrained · MANE · 4,180 bp · p 0.019 · regional, not allelic
Overall
CADD	21.8	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 0.00133% African / African-American · 1/75,040 alleles

Overall 6.84e-05% 1/1,461,876 alleles · very rare

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: TSLP
Protein: p.Ser92Trp
Coding: c.275C>G
MANE Select: NM_033035
dbSNP: rs1267224802
Type: single nucleotide variant
Location: chr5:111073569 (GRCh38)
Gene constraint: LOEUF 1.429 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.95 · 5 PDB
Residue 92: an α-helix; a disulfide bond

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

Similar variants

TSLP p.Arg149Cys Uncertain significance ★ ⚠ same type
TSLP p.Arg149His Uncertain significance ★ ⚠ same type
TSLP p.Asp35Asn Uncertain significance ★ ⚠ same type
TSLP p.Cys137Ser Uncertain significance ★ ⚠ same type
TSLP p.Gln140Lys Uncertain significance ★ ⚠ same type
TSLP p.Gly24Arg Uncertain significance ★ ⚠ same type
TSLP p.Leu22Pro Uncertain significance ★ ⚠ same type
TSLP p.Leu7Gln 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/tslp-p-ser92trp (accessed [today's date]).

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