Is F5 p.Leu85Arg (c.254T>G) pathogenic?

F5 p.Leu85Arg (c.254T>G) is classified Uncertain significance in F5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-07-11). AlphaMissense: likely pathogenic (0.7476); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with F5 p.Leu85Arg (c.254T>G)?

F5 p.Leu85Arg (c.254T>G) is associated with Inborn genetic diseases (ClinVar).

How common is F5 p.Leu85Arg (c.254T>G) in the general population?

F5 p.Leu85Arg (c.254T>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about F5 p.Leu85Arg (c.254T>G)?

AlphaMissense predicts likely pathogenic (score 0.7476) — an in-silico prediction, not a clinical call.

F5 p.Leu85Arg

c.254T>G · rs146656273 · VCV2507791

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7476 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7476	likely pathogenic
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -12.97	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	26.8	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 0.000509% European (non-Finnish) · 6/1,179,580 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,460,872 alleles · very 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.Leu85Arg
Coding: c.254T>G
MANE Select: NM_000130
dbSNP: rs146656273
Type: single nucleotide variant
Location: chr1:169572340 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 85: the f5/8 type a 1 domain; the plastocyanin-like 1 domain

Full F5 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

F5 p.Arg441His Uncertain significance ★★ ⚠ same condition
F5 p.Asn1559Ser Uncertain significance ★★ ⚠ same condition
F5 p.Asn1575Ser Uncertain significance ★★ ⚠ same condition
F5 p.Asp1739Gly Uncertain significance ★★ ⚠ same condition
F5 p.Glu2029Asp Uncertain significance ★★ ⚠ same condition
F5 p.Glu48Gln Uncertain significance ★★ ⚠ same condition
F5 p.His812Tyr Uncertain significance ★★ ⚠ same condition
F5 p.Ile1558Val 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/f5-p-leu85arg (accessed [today's date]).

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