Is F5 p.Ala249Val (c.746C>T) pathogenic?

F5 p.Ala249Val (c.746C>T) is classified Uncertain significance in F5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: likely benign (0.1937); Very rare (popmax 0.00017%, nfe).

How common is F5 p.Ala249Val (c.746C>T) in the general population?

F5 p.Ala249Val (c.746C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about F5 p.Ala249Val (c.746C>T)?

AlphaMissense predicts likely benign (score 0.1937) — an in-silico prediction, not a clinical call.

F5 p.Ala249Val

c.746C>T · VCV3339076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1937	likely benign
REVEL	0.69	pathogenic-leaning
SaProt	LLR -3.08	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	24.6	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,940 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,824 alleles · very rare exomes 2/1,461,564 · genomes 0/152,260 · 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: F5
Protein: p.Ala249Val
Coding: c.746C>T
MANE Select: NM_000130
Type: single nucleotide variant
Location: chr1:169556852 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 249: the f5/8 type a 1 domain; the plastocyanin-like 2 domain

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

Similar variants

F5 p.Ala249= Likely benign ★ 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-ala249val (accessed [today's date]).

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