Is F8 p.Val418Ala (c.1253T>C) pathogenic?

F8 p.Val418Ala (c.1253T>C) is classified Uncertain significance in F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.1037); Ultra-rare (popmax 0.023%, mid); Associated with Inborn genetic diseases.

What condition is associated with F8 p.Val418Ala (c.1253T>C)?

F8 p.Val418Ala (c.1253T>C) is associated with Inborn genetic diseases (ClinVar).

How common is F8 p.Val418Ala (c.1253T>C) in the general population?

F8 p.Val418Ala (c.1253T>C) is ultra-rare (popmax 0.023%, mid) (gnomAD).

What do computational predictors say about F8 p.Val418Ala (c.1253T>C)?

AlphaMissense predicts likely benign (score 0.1037) — an in-silico prediction, not a clinical call.

F8 p.Val418Ala

c.1253T>C · VCV4619067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1037 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1037	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -5.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.7	GERP -1
Regional constraint	o/e 0.74	unconstrained · MANE · 38 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	1.367	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 0.023% Middle Eastern · 1/4,355 alleles

Overall 8.25e-05% 1/1,211,525 alleles · ultra-rare exomes 1/1,098,050 · genomes 0/113,475 · 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: F8
Protein: p.Val418Ala
Coding: c.1253T>C
MANE Select: NM_000132
Type: single nucleotide variant
Location: chrX:154966444 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 418: the plastocyanin-like 3 domain; the f5/8 type a 2 domain

Full F8 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

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F8 p.Gly1729Trp Uncertain significance ★★ ⚠ same condition
F8 p.Leu13Phe Uncertain significance ★★ ⚠ same condition
F8 p.Ser1968Asn Uncertain significance ★★ ⚠ same condition
F8 p.Thr1670Ile 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/f8-p-val418ala (accessed [today's date]).

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