Is TACSTD2 p.Arg135Leu (c.404G>T) pathogenic?

TACSTD2 p.Arg135Leu (c.404G>T) is classified Uncertain significance in TACSTD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-11). AlphaMissense: likely pathogenic (0.7834); Ultra-rare (popmax 0.0197%, nfe).

How common is TACSTD2 p.Arg135Leu (c.404G>T) in the general population?

TACSTD2 p.Arg135Leu (c.404G>T) is ultra-rare (popmax 0.0197%, nfe) (gnomAD).

What do computational predictors say about TACSTD2 p.Arg135Leu (c.404G>T)?

AlphaMissense predicts likely pathogenic (score 0.7834) — an in-silico prediction, not a clinical call.

TACSTD2 p.Arg135Leu

c.404G>T · rs201254365 · VCV3173361

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7834 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7834	likely pathogenic
REVEL	0.559	indeterminate
SaProt	LLR -13.29	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.1, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 968 bp · p 0.067 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.0197% European (non-Finnish) · 232/1,178,864 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0168%

Overall 0.0151% 241/1,599,084 alleles · ultra-rare exomes 232/1,446,946 · genomes 9/152,138 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0197%	5,081
Remaining individualsnot grpmax-eligible	0.00803%	12,452
African / African-American	0.00401%	24,951
Admixed American	0.00167%	59,744

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: TACSTD2
Protein: p.Arg135Leu
Coding: c.404G>T
MANE Select: NM_002353
dbSNP: rs201254365
Type: single nucleotide variant
Location: chr1:58576753 (GRCh38)
Gene constraint: LOEUF 1.868 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.11 · 7 PDB
Residue 135: the thyroglobulin type-1 domain

Full TACSTD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TACSTD2 p.Arg135Cys Uncertain significance ★ ⚠ same residue
TACSTD2 c.-56C>G Uncertain significance ★★ same type
TACSTD2 p.Gly276Asp Uncertain significance ★★ ⚠ same type
TACSTD2 p.Gly59Ser Uncertain significance ★★ ⚠ same type
TACSTD2 c.-169G>A Benign ★★ same type
TACSTD2 c.-54A>C Benign ★★ same type
TACSTD2 c.*202A>G Benign ★★ same type
TACSTD2 c.*280T>C Benign ★★ 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/tacstd2-p-arg135leu (accessed [today's date]).

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