Is TMLHE p.Arg77Gln (c.230G>A) pathogenic?

TMLHE p.Arg77Gln (c.230G>A) is classified Uncertain significance in TMLHE (ClinVar, Single submitter, 3 submitters; last evaluated 2019-01-07). AlphaMissense: likely pathogenic (0.6717); Ultra-rare (popmax 0.0108%, nfe).

How common is TMLHE p.Arg77Gln (c.230G>A) in the general population?

TMLHE p.Arg77Gln (c.230G>A) is ultra-rare (popmax 0.0108%, nfe) (gnomAD).

What do computational predictors say about TMLHE p.Arg77Gln (c.230G>A)?

AlphaMissense predicts likely pathogenic (score 0.6717) — an in-silico prediction, not a clinical call.

TMLHE p.Arg77Gln

c.230G>A · rs373294094 · VCV1297623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6717 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6717	likely pathogenic
REVEL	0.841	moderately pathogenic-leaning
SaProt	LLR -11.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.55 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.3	GERP 2.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	25.0	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 0.0108% European (non-Finnish) · 96/891,071 alleles

Filtering AF 0.00901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00838%

Overall 0.00824% 99/1,201,523 alleles · ultra-rare exomes 98/1,089,718 · genomes 1/111,805 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0108%	9,282
Remaining individualsnot grpmax-eligible	0.00423%	23,625
South Asian	0.00183%	54,563

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.Arg77Gln
Coding: c.230G>A
MANE Select: NM_018196
dbSNP: rs373294094
Type: single nucleotide variant
Location: chrX:155524584 (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 residue
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-arg77gln (accessed [today's date]).

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