Is TMLHE p.Ala38Val (c.113C>T) pathogenic?

TMLHE p.Ala38Val (c.113C>T) is classified Uncertain significance in TMLHE (ClinVar, Single submitter, 1 submitter; last evaluated 2019-03-22). AlphaMissense: likely benign (0.0881); Very rare (popmax 0.00658%, amr).

How common is TMLHE p.Ala38Val (c.113C>T) in the general population?

TMLHE p.Ala38Val (c.113C>T) is very rare (popmax 0.00658%, amr) (gnomAD).

What do computational predictors say about TMLHE p.Ala38Val (c.113C>T)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

TMLHE p.Ala38Val

c.113C>T · rs781834884 · VCV928841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00658%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -6.77	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 0.39	GERP -0.72
Regional constraint	o/e 1.01	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	7.595	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00658% Admixed American · 3/45,587 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000884%

Overall 0.000248% 3/1,208,684 alleles · very rare exomes 2/1,096,588 · genomes 1/112,096 · joint denominator

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.Ala38Val
Coding: c.113C>T
MANE Select: NM_018196
dbSNP: rs781834884
Type: single nucleotide variant
Location: chrX:155545164 (GRCh38)
Structure: AlphaFold pLDDT 89.10

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

Similar variants

TMLHE p.Arg77Ter Uncertain significance ★★ same type
TMLHE p.Arg93His 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-ala38val (accessed [today's date]).

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