Is TMLHE p.Arg93Cys (c.277C>T) pathogenic?

TMLHE p.Arg93Cys (c.277C>T) is classified Uncertain significance in TMLHE (ClinVar, Single submitter, 3 submitters; last evaluated 2024-11-22). AlphaMissense: likely pathogenic (0.8452); Very rare (popmax 0.00525%, afr); Associated with isolated cerebellar hypoplasia/agenesis.

What condition is associated with TMLHE p.Arg93Cys (c.277C>T)?

TMLHE p.Arg93Cys (c.277C>T) is associated with isolated cerebellar hypoplasia/agenesis, corpus callosum, agenesis of (ClinVar).

How common is TMLHE p.Arg93Cys (c.277C>T) in the general population?

TMLHE p.Arg93Cys (c.277C>T) is very rare (popmax 0.00525%, afr) (gnomAD).

What do computational predictors say about TMLHE p.Arg93Cys (c.277C>T)?

AlphaMissense predicts likely pathogenic (score 0.8452) — an in-silico prediction, not a clinical call.

TMLHE p.Arg93Cys

c.277C>T · rs782785654 · VCV632605

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8452 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00525%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated cerebellar hypoplasia/agenesis

Computational evidence

Protein change
AlphaMissense	0.8452	likely pathogenic
REVEL	0.731	pathogenic-leaning
SaProt	LLR -13.49	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 3.3	GERP 3.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	24.0	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 0.00525% African / African-American · 3/57,180 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000686%

Overall 0.00108% 13/1,208,155 alleles · very rare exomes 11/1,096,008 · genomes 2/112,147 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00525%	19,060
South Asian	0.00356%	28,123
European (non-Finnish)	0.000895%	111,782

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: TMLHE
Protein: p.Arg93Cys
Coding: c.277C>T
MANE Select: NM_018196
dbSNP: rs782785654
Type: single nucleotide variant
Location: chrX:155524537 (GRCh38)
Structure: AlphaFold pLDDT 89.10

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

Disease context

isolated cerebellar hypoplasia/agenesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: corpus callosum, agenesis of

Similar variants

TMLHE p.Arg93His Uncertain significance ★★ ⚠ same residue
TMLHE p.Arg77Ter Uncertain significance ★★ same type
TMLHE p.Glu175Lys Uncertain significance ★★ ⚠ same type
TMLHE p.Glu369Asp Uncertain significance ★★ ⚠ same type
TMLHE p.Pro29Ala Uncertain significance ★★ ⚠ same type
TMLHE p.Thr265Ile Uncertain significance ★★ ⚠ same type
TMLHE p.Trp53Ter Uncertain significance ★★ same type
TMLHE p.Gly266= Likely 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/tmlhe-p-arg93cys (accessed [today's date]).

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