Is TRPM1 p.Pro780Ser (c.2338C>T) pathogenic?

TRPM1 p.Pro780Ser (c.2338C>T) is classified Uncertain significance in TRPM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-12). AlphaMissense: likely pathogenic (0.8955); Very rare (popmax 0.00659%, sas); Associated with Inborn genetic diseases.

What condition is associated with TRPM1 p.Pro780Ser (c.2338C>T)?

TRPM1 p.Pro780Ser (c.2338C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TRPM1 p.Pro780Ser (c.2338C>T) in the general population?

TRPM1 p.Pro780Ser (c.2338C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about TRPM1 p.Pro780Ser (c.2338C>T)?

AlphaMissense predicts likely pathogenic (score 0.8955) — an in-silico prediction, not a clinical call.

TRPM1 p.Pro780Ser

c.2338C>T · rs751792952 · VCV1062347

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8955 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8955	likely pathogenic
REVEL	0.735	pathogenic-leaning
SaProt	LLR -12.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 53 kb · p 0.68 · regional, not allelic
Overall
CADD	24.7	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P758S vs ClinVar P780S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,066 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000496% 8/1,613,906 alleles · very rare exomes 7/1,461,750 · genomes 1/152,156 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,178
European (non-Finnish)	0.00017%	589,971

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: TRPM1
Protein: p.Pro780Ser
Coding: c.2338C>T
MANE Select: NM_001252024
dbSNP: rs751792952
Type: single nucleotide variant
Location: chr15:31038145 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 66.74

Full TRPM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRPM1 p.Pro780Leu Uncertain significance ★ ⚠ same residue
TRPM1 p.Ala1240Pro Uncertain significance ★★ ⚠ same condition
TRPM1 p.Ala1364Val Uncertain significance ★★ ⚠ same condition
TRPM1 p.Ala1371Pro Uncertain significance ★★ ⚠ same condition
TRPM1 p.Ala1453Asp Uncertain significance ★★ ⚠ same condition
TRPM1 p.Ala150Ser Uncertain significance ★★ ⚠ same condition
TRPM1 p.Ala1534Thr Uncertain significance ★★ ⚠ same condition
TRPM1 p.Arg1063Trp Uncertain significance ★★ ⚠ same condition

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/trpm1-p-pro780ser (accessed [today's date]).

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