Is TES p.Cys46Arg (c.136T>C) pathogenic?

TES p.Cys46Arg (c.136T>C) is classified Uncertain significance in TES (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-29). AlphaMissense: likely pathogenic (0.9992); Very rare (popmax 0.00409%, nfe).

How common is TES p.Cys46Arg (c.136T>C) in the general population?

TES p.Cys46Arg (c.136T>C) is very rare (popmax 0.00409%, nfe) (gnomAD).

What do computational predictors say about TES p.Cys46Arg (c.136T>C)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

TES p.Cys46Arg

c.136T>C · rs771823352 · VCV2524001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00409%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic · top 1% in TES
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -12.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 47 kb · p 0.022 · regional, not allelic
Overall
CADD	28.8	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 0.00409% European (non-Finnish) · 48/1,173,544 alleles

Filtering AF 0.00317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0028%

Overall 0.00318% 51/1,602,988 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00409%	24,449
Admixed American	0.00342%	29,217
Remaining individualsnot grpmax-eligible	0.00161%	61,988

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: TES
Protein: p.Cys46Arg
Coding: c.136T>C
MANE Select: NM_015641
dbSNP: rs771823352
Type: single nucleotide variant
Location: chr7:116249042 (GRCh38)
Gene constraint: LOEUF 1.12 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.97 · 2 PDB

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

Similar variants

TES p.Ala186Val Uncertain significance ★ ⚠ same type
TES p.Ala227Thr Uncertain significance ★ ⚠ same type
TES p.Ala384Thr Uncertain significance ★ ⚠ same type
TES p.Ala77Thr Uncertain significance ★ ⚠ same type
TES p.Arg374Trp Uncertain significance ★ ⚠ same type
TES p.Arg89Cys Uncertain significance ★ ⚠ same type
TES p.Asn107Asp Uncertain significance ★ ⚠ same type
TES p.Asp345Tyr 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/tes-p-cys46arg (accessed [today's date]).

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