Is TMLHE p.Gln280Arg (c.839A>G) pathogenic?

TMLHE p.Gln280Arg (c.839A>G) is classified Uncertain significance in TMLHE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely benign (0.0797); Very rare (popmax 0.00592%, eas).

How common is TMLHE p.Gln280Arg (c.839A>G) in the general population?

TMLHE p.Gln280Arg (c.839A>G) is very rare (popmax 0.00592%, eas) (gnomAD).

What do computational predictors say about TMLHE p.Gln280Arg (c.839A>G)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

TMLHE p.Gln280Arg

c.839A>G · rs782761175 · VCV3179799

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00592%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0797	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -6.96	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 2.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	16.16	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 0.00592% East Asian · 2/33,801 alleles

Filtering AF 0.00098% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000367%

Overall 0.000248% 3/1,210,404 alleles · very rare exomes 3/1,097,057 · genomes 0/113,347 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00592%	16,901
European (non-Finnish)	0.000112%	894,510

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.Gln280Arg
Coding: c.839A>G
MANE Select: NM_018196
dbSNP: rs782761175
Type: single nucleotide variant
Location: chrX:155507054 (GRCh38)
Structure: AlphaFold pLDDT 89.10

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

Similar variants

TMLHE p.Gln280His 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-gln280arg (accessed [today's date]).

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