Is TSPEAR p.Val91Ile (c.271G>A) pathogenic?

TSPEAR p.Val91Ile (c.271G>A) is classified Likely benign in TSPEAR (ClinVar, Single submitter, 1 submitter; last evaluated 2016-06-21). AlphaMissense: likely benign (0.0932); Very rare (popmax 0.00525%, amr).

How common is TSPEAR p.Val91Ile (c.271G>A) in the general population?

TSPEAR p.Val91Ile (c.271G>A) is very rare (popmax 0.00525%, amr) (gnomAD).

What do computational predictors say about TSPEAR p.Val91Ile (c.271G>A)?

AlphaMissense predicts likely benign (score 0.0932) — an in-silico prediction, not a clinical call.

TSPEAR p.Val91Ile

c.271G>A · rs1555921926 · VCV505156

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00525%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0932	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -7.22	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 0.4	GERP -1.3, phastCons 0.046
Regional constraint	o/e 1.09	unconstrained · MANE · 212 kb · p 0.011 · regional, not allelic
Overall
CADD	7.8	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 0.00525% Admixed American · 3/57,182 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00281%

Overall 0.00332% 53/1,594,598 alleles · very rare exomes 51/1,442,442 · genomes 2/152,156 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00525%	19,061
European (non-Finnish)	0.00411%	24,357
Remaining individualsnot grpmax-eligible	0.00162%	61,634
African / African-American	0.00135%	74,244

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: TSPEAR
Protein: p.Val91Ile
Coding: c.271G>A
MANE Select: NM_144991
dbSNP: rs1555921926
Type: single nucleotide variant
Location: chr21:44567817 (GRCh38)
Gene constraint: LOEUF 1.161 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.47
Residue 91: the laminin g-like domain

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

Similar variants

TSPEAR c.1336+2T>A Pathogenic/Likely pathogenic ★★ same type
TSPEAR c.1337-2A>G Likely pathogenic ★★ same type
TSPEAR c.1856+2T>C Pathogenic/Likely pathogenic ★★ same type
TSPEAR p.Arg144Ter Pathogenic ★★ same type
TSPEAR p.Arg197Ter Pathogenic/Likely pathogenic ★★ same type
TSPEAR p.Gln365Ter Pathogenic ★★ same type
TSPEAR p.Gln79Ter Pathogenic/Likely pathogenic ★★ same type
TSPEAR p.Met1Thr Pathogenic ★★ 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/tspear-p-val91ile (accessed [today's date]).

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