Is TMLHE p.Val74Ile (c.220G>A) pathogenic?

TMLHE p.Val74Ile (c.220G>A) is classified Uncertain significance in TMLHE (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-16). AlphaMissense: likely benign (0.0974); Ultra-rare (popmax 0.0555%, amr).

How common is TMLHE p.Val74Ile (c.220G>A) in the general population?

TMLHE p.Val74Ile (c.220G>A) is ultra-rare (popmax 0.0555%, amr) (gnomAD).

What do computational predictors say about TMLHE p.Val74Ile (c.220G>A)?

AlphaMissense predicts likely benign (score 0.0974) — an in-silico prediction, not a clinical call.

TMLHE p.Val74Ile

c.220G>A · VCV4882445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0974 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0555%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0974	likely benign
REVEL	0.456	indeterminate
SaProt	LLR -6.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.7	GERP 3.4, phastCons 0.85
Regional constraint	o/e 1.01	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	21.8	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 0.0555% Admixed American · 25/45,063 alleles

Filtering AF 0.0385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0329%

Overall 0.0244% 293/1,201,428 alleles · ultra-rare exomes 266/1,089,502 · genomes 27/111,926 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0555%	1,803
European (non-Finnish)	0.0275%	3,636
Middle Eastern	0.0232%	4,319
Remaining individualsnot grpmax-eligible	0.0212%	4,727
Finnishnot grpmax-eligible	0.0129%	7,727
African / African-American	0.00526%	18,999
South Asian	0.00367%	27,283
East Asian	0.00299%	33,445

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.Val74Ile
Coding: c.220G>A
MANE Select: NM_018196
Type: single nucleotide variant
Location: chrX:155524594 (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-val74ile (accessed [today's date]).

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