Is TMLHE p.Ile313Phe (c.937A>T) pathogenic?

TMLHE p.Ile313Phe (c.937A>T) is classified Uncertain significance in TMLHE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). AlphaMissense: likely benign (0.182); Very rare (popmax 0.0047%, nfe).

How common is TMLHE p.Ile313Phe (c.937A>T) in the general population?

TMLHE p.Ile313Phe (c.937A>T) is very rare (popmax 0.0047%, nfe) (gnomAD).

What do computational predictors say about TMLHE p.Ile313Phe (c.937A>T)?

AlphaMissense predicts likely benign (score 0.182) — an in-silico prediction, not a clinical call.

TMLHE p.Ile313Phe

c.937A>T · VCV4597000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.182 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0047%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.182	likely benign
REVEL	0.462	indeterminate
SaProt	LLR -7.65	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 2.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 15 kb · p 0.00014 · regional, not allelic
Overall
CADD	21.1	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 0.0047% European (non-Finnish) · 42/894,049 alleles

Filtering AF 0.00352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00364% 44/1,208,001 alleles · very rare exomes 40/1,097,082 · genomes 4/110,919 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0047%	21,287
Remaining individualsnot grpmax-eligible	0.00421%	23,757

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.Ile313Phe
Coding: c.937A>T
MANE Select: NM_018196
Type: single nucleotide variant
Location: chrX:155506956 (GRCh38)
Structure: AlphaFold pLDDT 89.10

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

Similar variants

TMLHE p.Ile313Thr 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-ile313phe (accessed [today's date]).

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