Is F5 p.Ser1376Pro (c.4126T>C) pathogenic?

F5 p.Ser1376Pro (c.4126T>C) is classified Uncertain significance in F5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-05). AlphaMissense: likely benign (0.0939); Very rare (popmax 0.00847%, amr); Associated with Inborn genetic diseases.

What condition is associated with F5 p.Ser1376Pro (c.4126T>C)?

F5 p.Ser1376Pro (c.4126T>C) is associated with Inborn genetic diseases (ClinVar).

How common is F5 p.Ser1376Pro (c.4126T>C) in the general population?

F5 p.Ser1376Pro (c.4126T>C) is very rare (popmax 0.00847%, amr) (gnomAD).

What do computational predictors say about F5 p.Ser1376Pro (c.4126T>C)?

AlphaMissense predicts likely benign (score 0.0939) — an in-silico prediction, not a clinical call.

F5 p.Ser1376Pro

c.4126T>C · rs199739353 · VCV2381778

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0939 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00847%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0939	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -9.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP 1.4
Regional constraint	o/e 1.08	unconstrained · MANE · 679 bp · p 0.18 · regional, not allelic
Overall
CADD	3.379	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 0.00847% Admixed American · 5/59,030 alleles

Filtering AF 0.00327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.000627% 10/1,595,708 alleles · very rare exomes 4/1,443,508 · genomes 6/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00847%	11,806
Remaining individualsnot grpmax-eligible	0.00488%	20,471
African / African-American	0.00134%	74,510
European (non-Finnish)	8.58e-05%	1,166,148

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.Ser1376Pro
Coding: c.4126T>C
MANE Select: NM_000130
dbSNP: rs199739353
Type: single nucleotide variant
Location: chr1:169540964 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB
Residue 1376: the 'b' region; the '35 x 9 aa approximate tandem repeats of [tnp]-l-s-p-d-l-s-q-t' region

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-ser1376pro (accessed [today's date]).

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