Is FZD7 p.Pro514Ser (c.1540C>T) pathogenic?

FZD7 p.Pro514Ser (c.1540C>T) is classified Uncertain significance in FZD7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: likely benign (0.1782); Very rare (popmax 8.47e-05%, nfe).

How common is FZD7 p.Pro514Ser (c.1540C>T) in the general population?

FZD7 p.Pro514Ser (c.1540C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about FZD7 p.Pro514Ser (c.1540C>T)?

AlphaMissense predicts likely benign (score 0.1782) — an in-silico prediction, not a clinical call.

FZD7 p.Pro514Ser

c.1540C>T · VCV4670295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1782 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1782	likely benign
REVEL	0.443	indeterminate
SaProt	LLR -9.60	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 1,721 bp · p 0.00011 · regional, not allelic
Overall
CADD	24.5	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 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 6.2e-05% 1/1,613,514 alleles · very rare exomes 1/1,461,172 · genomes 0/152,342 · joint denominator

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: FZD7
Protein: p.Pro514Ser
Coding: c.1540C>T
MANE Select: NM_003507
Type: single nucleotide variant
Location: chr2:202036187 (GRCh38)
Gene constraint: LOEUF 0.781 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 13 PDB
Residue 514: an α-helix

Full FZD7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FZD7 p.Gly196Glu Benign ★★ same type
FZD7 p.Gly409= Benign ★★ same type
FZD7 p.Ala133Ser Uncertain significance ★ ⚠ same type
FZD7 p.Ala182Thr Uncertain significance ★ ⚠ same type
FZD7 p.Ala205Pro Uncertain significance ★ ⚠ same type
FZD7 p.Ala205Val Uncertain significance ★ ⚠ same type
FZD7 p.Ala253Thr Uncertain significance ★ same type
FZD7 p.Ala253Val 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/fzd7-p-pro514ser (accessed [today's date]).

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