Is MTTP p.Asn649Ser (c.1946A>G) pathogenic?

MTTP p.Asn649Ser (c.1946A>G) is classified Uncertain significance in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-01). AlphaMissense: likely benign (0.1243); Absent from gnomAD v4.1.

How common is MTTP p.Asn649Ser (c.1946A>G) in the general population?

MTTP p.Asn649Ser (c.1946A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MTTP p.Asn649Ser (c.1946A>G)?

AlphaMissense predicts likely benign (score 0.1243) — an in-silico prediction, not a clinical call.

MTTP p.Asn649Ser

c.1946A>G · VCV3366552

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1243 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1243	likely benign
REVEL	0.649	pathogenic-leaning
SaProt	LLR -7.80	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	22.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MTTP
Protein: p.Asn649Ser
Coding: c.1946A>G
MANE Select: NM_001386140
Type: single nucleotide variant
Location: chr4:99611410 (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 649: the vitellogenin domain; a UniProt-annotated variant site (in abl; uncertain significance; does not reduce interaction with p4hb/pdi and apob; reduces triglyceride transfer activity); a β-strand

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

Similar variants

MTTP p.Asn649= Likely benign ★ same residue
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

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-asn649ser (accessed [today's date]).

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