Is TRPV5 p.Pro243Ser (c.727C>T) pathogenic?

TRPV5 p.Pro243Ser (c.727C>T) is classified Uncertain significance in TRPV5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-24). AlphaMissense: likely benign (0.1968); Ultra-rare (popmax 0.0165%, mid).

How common is TRPV5 p.Pro243Ser (c.727C>T) in the general population?

TRPV5 p.Pro243Ser (c.727C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TRPV5 p.Pro243Ser (c.727C>T)?

AlphaMissense predicts likely benign (score 0.1968) — an in-silico prediction, not a clinical call.

TRPV5 p.Pro243Ser

c.727C>T · rs1436631191 · VCV2296618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1968 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1968	likely benign
REVEL	0.722	pathogenic-leaning
SaProt	LLR -13.01	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 4.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 25 kb · p 0.85 · regional, not allelic
Overall
CADD	27.1	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00031% 5/1,614,146 alleles · ultra-rare exomes 5/1,461,844 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00167%	60,016
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000169%	590,005

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: TRPV5
Protein: p.Pro243Ser
Coding: c.727C>T
MANE Select: NM_019841
dbSNP: rs1436631191
Type: single nucleotide variant
Location: chr7:142928726 (GRCh38)
Gene constraint: LOEUF 1.007 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.87 · 1 PDB

Full TRPV5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRPV5 p.Pro243Arg Uncertain significance ★ ⚠ same residue
TRPV5 p.Arg263Trp Benign ★★ ⚠ same type
TRPV5 p.Leu23Pro Benign ★★ same type
TRPV5 p.Ala102Thr Uncertain significance ★ ⚠ same type
TRPV5 p.Ala114Thr Uncertain significance ★ ⚠ same type
TRPV5 p.Ala191Thr Uncertain significance ★ ⚠ same type
TRPV5 p.Ala247Val Uncertain significance ★ ⚠ same type
TRPV5 p.Ala376Ser 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/trpv5-p-pro243ser (accessed [today's date]).

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