Is F7 p.Ile178Ser (c.533T>G) pathogenic?

F7 p.Ile178Ser (c.533T>G) is classified Conflicting classifications of pathogenicity in F7 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.1558); Rare (popmax 0.654%, afr); Associated with congenital factor VII deficiency.

What condition is associated with F7 p.Ile178Ser (c.533T>G)?

F7 p.Ile178Ser (c.533T>G) is associated with congenital factor VII deficiency (ClinVar).

How common is F7 p.Ile178Ser (c.533T>G) in the general population?

F7 p.Ile178Ser (c.533T>G) is rare (popmax 0.654%, afr) (gnomAD).

How is Congenital factor VII deficiency inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about F7 p.Ile178Ser (c.533T>G)?

AlphaMissense predicts likely benign (score 0.1558) — an in-silico prediction, not a clinical call.

F7 p.Ile178Ser

c.533T>G · rs141219108 · VCV1685780

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1558 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.654%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital factor VII deficiency

Computational evidence

Protein change
AlphaMissense	0.1558	likely benign
REVEL	0.628	indeterminate
SaProt	LLR -7.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.20	acceptor loss, 27 bp away · masked 0 · deltas
Pangolin	Δ0.22	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.1	GERP 0.54, phastCons 0.76
Regional constraint	o/e 0.95	unconstrained · MANE · 13 kb · p 0.22 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I200S vs ClinVar I178S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.654% African / African-American · 491/75,078 alleles

Filtering AF 0.606% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.587%

Overall 0.0332% 536/1,613,892 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.654%	153
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.032%	3,125
Admixed American	0.0283%	3,531
South Asian	0.0011%	91,088
European (non-Finnish)	0.000169%	589,974

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: F7
Protein: p.Ile178Ser
Coding: c.533T>G
MANE Select: NM_019616
dbSNP: rs141219108
Type: single nucleotide variant
Location: chr13:113116793 (GRCh38)
Gene constraint: LOEUF 1.113 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.64 · 114 PDB
Residue 178: a β-strand; a disulfide bond; the egf-like 2 domain

Full F7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Congenital factor VII deficiency (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

F7 c.225+1G>C Pathogenic ★★ same condition
F7 c.364+1G>A Pathogenic/Likely pathogenic ★★ same condition
F7 c.505+78G>A Pathogenic/Likely pathogenic ★★ same condition
F7 c.615+1G>T Pathogenic/Likely pathogenic ★★ same condition
F7 c.739+1G>A Pathogenic/Likely pathogenic ★★ same condition
F7 c.-30A>C Likely pathogenic ★★ same condition
F7 c.-55C>T Pathogenic/Likely pathogenic ★★ same condition
F7 c.-61T>G Likely pathogenic ★★ 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/f7-p-ile178ser (accessed [today's date]).

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