Is F5 p.Ile2197Phe (c.6589A>T) pathogenic?

F5 p.Ile2197Phe (c.6589A>T) is classified Uncertain significance in F5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-01). AlphaMissense: likely benign (0.1729); Ultra-rare (popmax 0.0178%, eas).

How common is F5 p.Ile2197Phe (c.6589A>T) in the general population?

F5 p.Ile2197Phe (c.6589A>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about F5 p.Ile2197Phe (c.6589A>T)?

AlphaMissense predicts likely benign (score 0.1729) — an in-silico prediction, not a clinical call.

F5 p.Ile2197Phe

c.6589A>T · VCV3772424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1729 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1729	likely benign
REVEL	0.412	indeterminate
SaProt	LLR -5.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 2.4	GERP -1.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 26 kb · p 4.4e-06 · regional, not allelic
Overall
CADD	19.85	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 0.0178% East Asian · 8/44,858 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000496% 8/1,613,202 alleles · ultra-rare

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: F5
Protein: p.Ile2197Phe
Coding: c.6589A>T
MANE Select: NM_000130
Type: single nucleotide variant
Location: chr1:169514399 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 2197: a disulfide bond; a β-strand; the f5/8 type c 2 domain

Full F5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

F5 p.Ile2197Val Uncertain significance ★★ ⚠ same residue
F5 c.1297-2A>G Pathogenic/Likely pathogenic ★★ same type
F5 p.Arg1030Ter Pathogenic ★★ same type
F5 p.Arg146Ter Pathogenic/Likely pathogenic ★★ same type
F5 p.Arg1621Ter Pathogenic/Likely pathogenic ★★ same type
F5 p.Arg1634Ter Pathogenic/Likely pathogenic ★★ same type
F5 p.Arg2102His Pathogenic/Likely pathogenic ★★ same type
F5 p.Arg740Ter Pathogenic/Likely pathogenic ★★ 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/f5-p-ile2197phe (accessed [today's date]).

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