Is MASP2 p.Phe133Val (c.397T>G) pathogenic?

MASP2 p.Phe133Val (c.397T>G) is classified Uncertain significance in MASP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-16). AlphaMissense: ambiguous (0.4526); Rare (popmax 0.148%, mid).

How common is MASP2 p.Phe133Val (c.397T>G) in the general population?

MASP2 p.Phe133Val (c.397T>G) is rare (popmax 0.148%, mid) (gnomAD).

What do computational predictors say about MASP2 p.Phe133Val (c.397T>G)?

AlphaMissense predicts ambiguous (score 0.4526) — an in-silico prediction, not a clinical call.

MASP2 p.Phe133Val

c.397T>G · VCV4955185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4526 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4526	ambiguous
REVEL	0.243	benign-leaning
SaProt	LLR -7.37	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP -3.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 20 kb · p 0.39 · regional, not allelic
Overall
CADD	24.0	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 0.148% Middle Eastern · 9/6,062 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0947%

Overall 0.00744% 120/1,613,940 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.148%	674
African / African-American	0.123%	816
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed American	0.005%	20,009
European (non-Finnish)	0.000254%	393,342

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: MASP2
Protein: p.Phe133Val
Coding: c.397T>G
MANE Select: NM_006610
Type: single nucleotide variant
Location: chr1:11046571 (GRCh38)
Gene constraint: LOEUF 1.159 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.73 · 10 PDB
Residue 133: the cub 1 domain; a β-strand

Full MASP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MASP2 p.Arg376Ter Likely pathogenic ★★ same type
TARDBP p.Gly294Val Pathogenic/Likely pathogenic ★★ ⚠ same type
MASP2 p.Ala149Val Uncertain significance ★★ ⚠ same type
MASP2 p.Ala169Gly Uncertain significance ★★ ⚠ same type
MASP2 p.Arg29His Uncertain significance ★★ ⚠ same type
MASP2 p.Arg58Cys Uncertain significance ★★ ⚠ same type
MASP2 p.Asp75Asn Uncertain significance ★★ ⚠ same type
MASP2 p.Cys396Tyr Uncertain significance ★★ ⚠ 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/masp2-p-phe133val (accessed [today's date]).

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