Is TMLHE p.Gln280His (c.840G>T) pathogenic?

TMLHE p.Gln280His (c.840G>T) is classified Uncertain significance in TMLHE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely benign (0.1935); Very rare (popmax 0.00701%, afr).

How common is TMLHE p.Gln280His (c.840G>T) in the general population?

TMLHE p.Gln280His (c.840G>T) is very rare (popmax 0.00701%, afr) (gnomAD).

What do computational predictors say about TMLHE p.Gln280His (c.840G>T)?

AlphaMissense predicts likely benign (score 0.1935) — an in-silico prediction, not a clinical call.

TMLHE p.Gln280His

c.840G>T · rs199989202 · VCV3179800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00701%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1935	likely benign
REVEL	0.403	indeterminate
SaProt	LLR -11.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.77	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00701% African / African-American · 4/57,035 alleles

Filtering AF 0.00234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00187%

Overall 0.0029% 35/1,208,196 alleles · very rare exomes 30/1,097,087 · genomes 5/111,109 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00701%	14,259
Admixed American	0.00439%	22,776
European (non-Finnish)	0.00313%	31,931
Remaining individualsnot grpmax-eligible	0.0021%	47,526

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.Gln280His
Coding: c.840G>T
MANE Select: NM_018196
dbSNP: rs199989202
Type: single nucleotide variant
Location: chrX:155507053 (GRCh38)
Structure: AlphaFold pLDDT 89.10

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

Similar variants

TMLHE p.Gln280Arg Uncertain significance ★ ⚠ same residue
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

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-gln280his (accessed [today's date]).

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