Is MTTP p.Ser303Pro (c.907T>C) pathogenic?

MTTP p.Ser303Pro (c.907T>C) is classified Uncertain significance in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-28). AlphaMissense: likely benign (0.0975); Very rare (popmax 0.00133%, afr).

How common is MTTP p.Ser303Pro (c.907T>C) in the general population?

MTTP p.Ser303Pro (c.907T>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MTTP p.Ser303Pro (c.907T>C)?

AlphaMissense predicts likely benign (score 0.0975) — an in-silico prediction, not a clinical call.

MTTP p.Ser303Pro

c.907T>C · rs1725516415 · VCV1399039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0975 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0975	likely benign
REVEL	0.442	indeterminate
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	23.2	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 0.00133% African / African-American · 1/75,022 alleles

Overall 6.84e-05% 1/1,461,522 alleles · very rare

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: MTTP
Protein: p.Ser303Pro
Coding: c.907T>C
MANE Select: NM_001386140
dbSNP: rs1725516415
Type: single nucleotide variant
Location: chr4:99594881 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.73 · 2 PDB
Residue 303: the vitellogenin domain

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

Similar variants

MTTP c.1067+1G>C Likely pathogenic ★★ same type
MTTP c.1236+1G>A Pathogenic/Likely pathogenic ★★ same type
MTTP c.1769+2T>C Pathogenic/Likely pathogenic ★★ same type
MTTP c.1867+1G>A Pathogenic ★★ same type
MTTP c.1867+5G>A Pathogenic/Likely pathogenic ★★ same type
MTTP c.1868-2A>G Likely pathogenic ★★ same type
MTTP c.2342+1G>A Pathogenic ★★ same type
MTTP c.502-1G>C Likely pathogenic ★★ 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/mttp-p-ser303pro (accessed [today's date]).

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