Is TSHB p.Val91Ala (c.272T>C) pathogenic?

TSHB p.Val91Ala (c.272T>C) is classified Uncertain significance in TSHB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). AlphaMissense: likely benign (0.1295); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TSHB p.Val91Ala (c.272T>C)?

TSHB p.Val91Ala (c.272T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TSHB p.Val91Ala (c.272T>C) in the general population?

TSHB p.Val91Ala (c.272T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSHB p.Val91Ala (c.272T>C)?

AlphaMissense predicts likely benign (score 0.1295) — an in-silico prediction, not a clinical call.

TSHB p.Val91Ala

c.272T>C · VCV3462798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1295 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1295	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -9.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 2.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 861 bp · p 0.3 · regional, not allelic
Overall
CADD	19.21	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSHB
Protein: p.Val91Ala
Coding: c.272T>C
MANE Select: NM_000549
Type: single nucleotide variant
Location: chr1:115034082 (GRCh38)
Gene constraint: LOEUF 1.532 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.28 · 3 PDB
Residue 91: a UniProt-annotated variant site (in chng4)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TSHB p.Ala100Thr Uncertain significance ★★ ⚠ same condition
TSHB p.Gly86Arg Uncertain significance ★★ ⚠ same condition
TSHB p.Arg54Gln Uncertain significance ★ ⚠ same condition
TSHB p.Arg75Lys Uncertain significance ★ ⚠ same condition
TSHB p.Asp55Gly Uncertain significance ★ ⚠ same condition
TSHB p.Ile46Phe Uncertain significance ★ ⚠ same condition
TSHB p.Ile84Met Uncertain significance ★ ⚠ same condition
TSHB p.Lys107Asn 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/tshb-p-val91ala (accessed [today's date]).

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