Is TMLHE p.Pro29Ala (c.85C>G) pathogenic?

TMLHE p.Pro29Ala (c.85C>G) is classified Uncertain significance in TMLHE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-09). AlphaMissense: likely benign (0.0638); Very rare (popmax 0.00353%, sas).

How common is TMLHE p.Pro29Ala (c.85C>G) in the general population?

TMLHE p.Pro29Ala (c.85C>G) is very rare (popmax 0.00353%, sas) (gnomAD).

What do computational predictors say about TMLHE p.Pro29Ala (c.85C>G)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

TMLHE p.Pro29Ala

c.85C>G · rs782385694 · VCV807879

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00353%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -6.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -1.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 38 kb · p 0.87 · regional, not allelic
Overall
CADD	0.988	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 0.00353% South Asian · 2/56,689 alleles

Filtering AF 0.000585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.000579% 7/1,208,615 alleles · very rare exomes 6/1,096,705 · genomes 1/111,910 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00353%	28,345
Admixed American	0.00219%	45,674
Remaining individualsnot grpmax-eligible	0.0021%	47,531
European (non-Finnish)	0.000335%	298,078

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.Pro29Ala
Coding: c.85C>G
MANE Select: NM_018196
dbSNP: rs782385694
Type: single nucleotide variant
Location: chrX:155545192 (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.Thr265Ile Uncertain significance ★★ ⚠ same type
TMLHE p.Trp53Ter Uncertain significance ★★ same type
TMLHE p.Gly266= Likely benign ★★ same type
TMLHE p.Leu111= 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-pro29ala (accessed [today's date]).

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