Is TRPM5 p.Pro44Leu (c.131C>T) pathogenic?

TRPM5 p.Pro44Leu (c.131C>T) is classified Likely benign in TRPM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: likely benign (0.1241); Very rare (popmax 0.00268%, afr).

How common is TRPM5 p.Pro44Leu (c.131C>T) in the general population?

TRPM5 p.Pro44Leu (c.131C>T) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about TRPM5 p.Pro44Leu (c.131C>T)?

AlphaMissense predicts likely benign (score 0.1241) — an in-silico prediction, not a clinical call.

TRPM5 p.Pro44Leu

c.131C>T · VCV4599652

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1241 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1241	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -9.25	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 7.7	GERP 0.68, phastCons 1
Overall
CADD	18.71	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 0.00268% African / African-American · 2/74,708 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00118% 19/1,610,774 alleles · very rare exomes 18/1,458,866 · genomes 1/151,908 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,191
African / African-Americangrpmax	0.00268%	37,354
Admixed American	0.00167%	59,860
European (non-Finnish)	0.0011%	90,692
South Asian	0.0011%	90,938

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TRPM5
Protein: p.Pro44Leu
Coding: c.131C>T
MANE Select: NM_014555
Type: single nucleotide variant
Location: chr11:2422308 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.66

Full TRPM5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPM5 p.Ala574= Benign ★★ same type
TRPM5 p.Arg500Gln Likely benign ★★ same type
TRPM5 p.Cys227= Benign ★★ same type
TRPM5 p.Gly1136Ser Benign ★★ same type
TRPM5 p.Pro455= Benign/Likely benign ★★ same type
TRPM5 p.Thr218= Benign ★★ same type
TRPM5 p.Thr314= Benign/Likely benign ★★ same type
TRPM5 p.Thr616= 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/trpm5-p-pro44leu (accessed [today's date]).

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