Is F8 p.Ala488Pro (c.1462G>C) pathogenic?

F8 p.Ala488Pro (c.1462G>C) is classified Likely pathogenic in F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-19). AlphaMissense: likely pathogenic (0.9215); Absent from gnomAD v4.1.

How common is F8 p.Ala488Pro (c.1462G>C) in the general population?

F8 p.Ala488Pro (c.1462G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F8 p.Ala488Pro (c.1462G>C)?

AlphaMissense predicts likely pathogenic (score 0.9215) — an in-silico prediction, not a clinical call.

F8 p.Ala488Pro

c.1462G>C · rs2523945705 · VCV2683582

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9215 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9215	likely pathogenic ✓ concordant with ClinVar · top 4% in F8
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -12.57	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 7.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 38 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	26.7	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: F8
Protein: p.Ala488Pro
Coding: c.1462G>C
MANE Select: NM_000132
dbSNP: rs2523945705
Type: single nucleotide variant
Location: chrX:154961150 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 488: the plastocyanin-like 3 domain; a UniProt-annotated variant site (in hema; moderate); a β-strand; the f5/8 type a 2 domain

Full F8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

F8 p.Ala488Ser Uncertain significance ★ ⚠ same residue
F8 c.6429+2T>A Pathogenic ★★★ same type
F8 p.Ala111Thr Likely pathogenic ★★★ same type
F8 p.Ala2220Pro Pathogenic ★★★ same type
F8 p.Ala415Asp Likely pathogenic ★★★ same type
F8 p.Ala415Val Pathogenic ★★★ ⚠ same type
F8 p.Arg1768His Pathogenic ★★★ ⚠ same type
F8 p.Arg1800His 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/f8-p-ala488pro (accessed [today's date]).

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