Is MFAP5 p.Pro46Ser (c.136C>T) pathogenic?

MFAP5 p.Pro46Ser (c.136C>T) is classified Uncertain significance in MFAP5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-22). AlphaMissense: ambiguous (0.3415); Ultra-rare (popmax 0.0165%, mid); Associated with Cardiovascular phenotype.

What condition is associated with MFAP5 p.Pro46Ser (c.136C>T)?

MFAP5 p.Pro46Ser (c.136C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is MFAP5 p.Pro46Ser (c.136C>T) in the general population?

MFAP5 p.Pro46Ser (c.136C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MFAP5 p.Pro46Ser (c.136C>T)?

AlphaMissense predicts ambiguous (score 0.3415) — an in-silico prediction, not a clinical call.

MFAP5 p.Pro46Ser

c.136C>T · rs373540219 · VCV1957667

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3415 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3415	ambiguous
REVEL	0.358	indeterminate
SaProt	LLR -5.98	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 14 kb · p 0.45 · 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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00124% 20/1,610,724 alleles · ultra-rare exomes 20/1,458,432 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,823
Admixed American	0.00333%	29,994
European (non-Finnish)	0.00119%	84,251

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: MFAP5
Protein: p.Pro46Ser
Coding: c.136C>T
MANE Select: NM_003480
dbSNP: rs373540219
Type: single nucleotide variant
Location: chr12:8655789 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.79

Full MFAP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MFAP5 p.Pro46Leu Uncertain significance ★ same residue
MFAP5 c.140-3C>A Uncertain significance ★★ same condition
MFAP5 c.335+4A>G Uncertain significance ★★ same condition
MFAP5 c.336-3C>T Uncertain significance ★★ same condition
MFAP5 p.Arg115His Uncertain significance ★★ same condition
MFAP5 p.Arg126His Uncertain significance ★★ same condition
MFAP5 p.Arg30Gln Uncertain significance ★★ ⚠ same condition
MFAP5 p.Arg93Ser 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/mfap5-p-pro46ser (accessed [today's date]).

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