Is F5 p.Arg376Ser (c.1128G>T) pathogenic?

F5 p.Arg376Ser (c.1128G>T) is classified Uncertain significance in F5 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-12-19). AlphaMissense: likely pathogenic (0.5867); Ultra-rare (popmax 0.0417%, mid); Associated with factor V deficiency.

What condition is associated with F5 p.Arg376Ser (c.1128G>T)?

F5 p.Arg376Ser (c.1128G>T) is associated with factor V deficiency, thrombophilia due to thrombin defect, thrombophilia due to activated protein C resistance (ClinVar).

How common is F5 p.Arg376Ser (c.1128G>T) in the general population?

F5 p.Arg376Ser (c.1128G>T) is ultra-rare (popmax 0.0417%, mid) (gnomAD).

What do computational predictors say about F5 p.Arg376Ser (c.1128G>T)?

AlphaMissense predicts likely pathogenic (score 0.5867) — an in-silico prediction, not a clinical call.

F5 p.Arg376Ser

c.1128G>T · rs373172802 · VCV627209

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.5867 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

factor V deficiency

Computational evidence

Protein change
AlphaMissense	0.5867	likely pathogenic
REVEL	0.6	indeterminate
SaProt	LLR -4.28	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.43	acceptor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.14	GERP -1.1, phastCons 0.85
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	19.1	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 0.0417% Middle Eastern · 2/4,794 alleles

Filtering AF 0.00886% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0083%

Overall 0.0087% 140/1,609,612 alleles · ultra-rare exomes 126/1,457,588 · genomes 14/152,024 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0417%	2,397
Remaining individualsnot grpmax-eligible	0.0193%	5,188
European (non-Finnish)	0.0104%	9,654
South Asian	0.0022%	45,447
Admixed American	0.00167%	59,966
African / African-American	0.00134%	74,724

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.Arg376Ser
Coding: c.1128G>T
MANE Select: NM_000130
dbSNP: rs373172802
Type: single nucleotide variant
Location: chr1:169552725 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 376: the f5/8 type a 2 domain; the plastocyanin-like 3 domain

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

Disease context

factor V deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to thrombin defect thrombophilia due to activated protein C resistance Budd-Chiari syndrome

Similar variants

F5 c.1297-2A>G Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg1030Ter Pathogenic ★★ same condition
F5 p.Arg740Ter Pathogenic/Likely pathogenic ★★ same condition
F5 p.Tyr1730Cys Pathogenic/Likely pathogenic ★★ same condition
F5 c.-110C>A Uncertain significance ★★ same condition
F5 p.Ala38Thr Uncertain significance ★★ ⚠ same condition
F5 p.Arg1715Gln Uncertain significance ★★ ⚠ same condition
F5 p.Arg2055Gln 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-arg376ser (accessed [today's date]).

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