Is FRMD5 p.Arg447Pro (c.1340G>C) pathogenic?

FRMD5 p.Arg447Pro (c.1340G>C) is classified Uncertain significance in FRMD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-27). AlphaMissense: ambiguous (0.3474); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with FRMD5 p.Arg447Pro (c.1340G>C)?

FRMD5 p.Arg447Pro (c.1340G>C) is associated with Inborn genetic diseases (ClinVar).

How common is FRMD5 p.Arg447Pro (c.1340G>C) in the general population?

FRMD5 p.Arg447Pro (c.1340G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FRMD5 p.Arg447Pro (c.1340G>C)?

AlphaMissense predicts ambiguous (score 0.3474) — an in-silico prediction, not a clinical call.

FRMD5 p.Arg447Pro

c.1340G>C · VCV3517238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3474 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3474	ambiguous
REVEL	0.41	indeterminate
SaProt	LLR -5.75	tolerated
Splicing
SpliceAI	Δ0.36	acceptor gain · deltas
Pangolin	Δ0.30	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 532 bp · p 0.24 · regional, not allelic
Overall
CADD	28.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FRMD5
Protein: p.Arg447Pro
Coding: c.1340G>C
MANE Select: NM_032892
Type: single nucleotide variant
Location: chr15:43874258 (GRCh38)
Gene constraint: LOEUF 0.488 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 75.79

Full FRMD5 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

FRMD5 p.Ala137Val Uncertain significance ★ ⚠ same condition
FRMD5 p.Ala274Thr Uncertain significance ★ same condition
FRMD5 p.Ala427Thr Uncertain significance ★ ⚠ same condition
FRMD5 p.Ala464Val Uncertain significance ★ ⚠ same condition
FRMD5 p.Arg336Gln Uncertain significance ★ ⚠ same condition
FRMD5 p.Arg350Gln Uncertain significance ★ ⚠ same condition
FRMD5 p.Arg360Ser Uncertain significance ★ ⚠ same condition
FRMD5 p.Arg384Gln 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/frmd5-p-arg447pro (accessed [today's date]).

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