Is MCFD2 p.Val46= (c.138G>A) pathogenic?

MCFD2 p.Val46= (c.138G>A) is classified Uncertain significance in MCFD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Rare (popmax 0.252%, eas); Associated with factor 5 and Factor VIII, combined deficiency of, 2.

What condition is associated with MCFD2 p.Val46= (c.138G>A)?

MCFD2 p.Val46= (c.138G>A) is associated with factor 5 and Factor VIII, combined deficiency of, 2 (ClinVar).

How common is MCFD2 p.Val46= (c.138G>A) in the general population?

MCFD2 p.Val46= (c.138G>A) is rare (popmax 0.252%, eas) (gnomAD).

How is Combined deficiency of factor V and factor VIII inherited?

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

MCFD2 p.Val46=

c.138G>A · rs766859640 · VCV895102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.252%, eas)

Conditions

factor 5 and Factor VIII, combined deficiency of, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.16	GERP -2.8, phastCons 0.4
Overall
CADD	8.572	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.252% East Asian · 113/44,884 alleles

Filtering AF 0.214% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.2%

Overall 0.00712% 115/1,614,236 alleles · rare exomes 111/1,461,872 · genomes 4/152,364 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.252%	397
Remaining individualsnot grpmax-eligible	0.0032%	31,254

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: MCFD2
Protein: p.Val46=
Coding: c.138G>A
MANE Select: NM_139279
dbSNP: rs766859640
Type: single nucleotide variant
Location: chr2:46909034 (GRCh38)
Gene constraint: LOEUF 1.366 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.97 · 17 PDB
Residue 46: an α-helix

Full MCFD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

factor 5 and Factor VIII, combined deficiency of, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined deficiency of factor V and factor VIII (Orphanet):

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

Similar variants

TTC7A p.Gly46Arg Uncertain significance ★ ⚠ same residue
TTC7A p.Gly46Asp Uncertain significance ★ ⚠ same residue
MCFD2 c.149+5G>A Likely pathogenic ★★ same condition
MCFD2 p.Ala139Val Uncertain significance ★★ same condition
MCFD2 p.Ile121Met Uncertain significance ★★ ⚠ same condition
MCFD2 c.310-11G>C Likely benign ★★ same condition
MCFD2 c.*1267G>T Benign ★★ same condition
MCFD2 c.*133A>T Benign ★★ 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/mcfd2-p-val46 (accessed [today's date]).

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