Is PIEZO1 p.Val2125Met (c.6373G>A) pathogenic?

PIEZO1 p.Val2125Met (c.6373G>A) is classified Uncertain significance in PIEZO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-01). AlphaMissense: likely pathogenic (0.8656); Very rare (popmax 0.00274%, afr); Associated with Inborn genetic diseases.

What condition is associated with PIEZO1 p.Val2125Met (c.6373G>A)?

PIEZO1 p.Val2125Met (c.6373G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PIEZO1 p.Val2125Met (c.6373G>A) in the general population?

PIEZO1 p.Val2125Met (c.6373G>A) is very rare (popmax 0.00274%, afr) (gnomAD).

What do computational predictors say about PIEZO1 p.Val2125Met (c.6373G>A)?

AlphaMissense predicts likely pathogenic (score 0.8656) — an in-silico prediction, not a clinical call.

PIEZO1 p.Val2125Met

c.6373G>A · VCV3888712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00274%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8656	likely pathogenic
REVEL	0.454	indeterminate
SaProt	LLR -10.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.7, phastCons 1
Regional constraint	o/e 1.45	unconstrained · MANE · 69 kb · p 1.1e-155 · regional, not allelic
Overall
CADD	26.3	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00274% African / African-American · 2/73,120 alleles

Filtering AF 0.000454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.000193% 3/1,553,506 alleles · very rare exomes 2/1,401,248 · genomes 1/152,258 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00274%	36,560
European (non-Finnish)	8.7e-05%	1,148,802

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: PIEZO1
Protein: p.Val2125Met
Coding: c.6373G>A
MANE Select: NM_001142864
Type: single nucleotide variant
Location: chr16:88719672 (GRCh38)
Gene constraint: LOEUF 1.17 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.74 · 6 PDB
Residue 2125: a UniProt-annotated variant site (found in er(a-b-) blood group phenotype); an α-helix

Full PIEZO1 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

PIEZO1 p.Val2125= Uncertain significance ★★ same residue
PIEZO1 p.Ala1080Thr Uncertain significance ★★ ⚠ same condition
PIEZO1 p.Ala1109Val Uncertain significance ★★ ⚠ same condition
PIEZO1 p.Ala1447Val Uncertain significance ★★ ⚠ same condition
PIEZO1 p.Ala1474Thr Uncertain significance ★★ ⚠ same condition
PIEZO1 p.Ala1498Thr Uncertain significance ★★ ⚠ same condition
PIEZO1 p.Ala1685Val Uncertain significance ★★ ⚠ same condition
PIEZO1 p.Ala1956Thr 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/piezo1-p-val2125met (accessed [today's date]).

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