Is MTTP p.Pro625Ser (c.1873C>T) pathogenic?

MTTP p.Pro625Ser (c.1873C>T) is classified Conflicting classifications of pathogenicity in MTTP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-08). AlphaMissense: likely benign (0.0681); Rare (popmax 0.139%, sas); Associated with Inborn genetic diseases.

What condition is associated with MTTP p.Pro625Ser (c.1873C>T)?

MTTP p.Pro625Ser (c.1873C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MTTP p.Pro625Ser (c.1873C>T) in the general population?

MTTP p.Pro625Ser (c.1873C>T) is rare (popmax 0.139%, sas) (gnomAD).

What do computational predictors say about MTTP p.Pro625Ser (c.1873C>T)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

MTTP p.Pro625Ser

c.1873C>T · rs531331759 · VCV2080853

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.139%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.29	GERP -3
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	3.712	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 0.139% South Asian · 127/91,084 alleles

Filtering AF 0.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.112%

Overall 0.00799% 129/1,614,058 alleles · rare exomes 126/1,461,800 · genomes 3/152,258 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.139%	717
Remaining individualsnot grpmax-eligible	0.0032%	31,253

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.Pro625Ser
Coding: c.1873C>T
MANE Select: NM_001386140
dbSNP: rs531331759
Type: single nucleotide variant
Location: chr4:99611337 (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 625: the vitellogenin domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MTTP p.Pro625Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MTTP p.Ala144Asp Uncertain significance ★★ ⚠ same condition
MTTP p.Ala339Val Uncertain significance ★★ ⚠ same condition
MTTP p.Ala464Thr Uncertain significance ★★ ⚠ same condition
MTTP p.Ala493Ser Uncertain significance ★★ ⚠ same condition
MTTP p.Ala577Thr Uncertain significance ★★ ⚠ same condition
MTTP p.Ala883Asp Uncertain significance ★★ ⚠ same condition
MTTP p.Arg312Gly 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/mttp-p-pro625ser (accessed [today's date]).

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