Is TSPEAR p.Arg669Cys (c.2005C>T) pathogenic?

TSPEAR p.Arg669Cys (c.2005C>T) is classified Uncertain significance in TSPEAR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). AlphaMissense: likely benign (0.2536); Ultra-rare (popmax 0.0188%, sas).

How common is TSPEAR p.Arg669Cys (c.2005C>T) in the general population?

TSPEAR p.Arg669Cys (c.2005C>T) is ultra-rare (popmax 0.0188%, sas) (gnomAD).

What do computational predictors say about TSPEAR p.Arg669Cys (c.2005C>T)?

AlphaMissense predicts likely benign (score 0.2536) — an in-silico prediction, not a clinical call.

TSPEAR p.Arg669Cys

c.2005C>T · VCV3901516

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2536 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2536	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -10.27	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.92	GERP -2.2
Regional constraint	o/e 1.09	unconstrained · MANE · 212 kb · p 0.011 · regional, not allelic
Overall
CADD	15.56	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 0.0188% South Asian · 16/85,272 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00955%

Overall 0.00172% 27/1,566,154 alleles · ultra-rare exomes 24/1,413,826 · genomes 3/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0188%	5,329
African / African-American	0.00272%	36,766
East Asian	0.00239%	41,846
European (non-Finnish)	0.000691%	144,623

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.Arg669Cys
Coding: c.2005C>T
MANE Select: NM_144991
Type: single nucleotide variant
Location: chr21:44499788 (GRCh38)
Gene constraint: LOEUF 1.161 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.47
Residue 669: a UniProt-annotated variant site (in ectd14 and sthag10); a UniProt-annotated variant site (in ectd14); a UniProt-annotated variant site (in sthag10)

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

Similar variants

TSPEAR p.Arg669His Uncertain significance ★★ ⚠ same residue
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

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-arg669cys (accessed [today's date]).

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