Is MTTP p.Ala339Glu (c.1016C>A) pathogenic?

MTTP p.Ala339Glu (c.1016C>A) is classified Uncertain significance in MTTP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-01). AlphaMissense: ambiguous (0.4626); Ultra-rare (popmax 0.0362%, nfe).

How common is MTTP p.Ala339Glu (c.1016C>A) in the general population?

MTTP p.Ala339Glu (c.1016C>A) is ultra-rare (popmax 0.0362%, nfe) (gnomAD).

What do computational predictors say about MTTP p.Ala339Glu (c.1016C>A)?

AlphaMissense predicts ambiguous (score 0.4626) — an in-silico prediction, not a clinical call.

MTTP p.Ala339Glu

c.1016C>A · rs137956833 · VCV1413365

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4626 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4626	ambiguous
REVEL	0.415	indeterminate
SaProt	LLR -9.44	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	23.8	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 0.0362% European (non-Finnish) · 427/1,179,870 alleles

Filtering AF 0.0333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0322%

Overall 0.0275% 443/1,613,628 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0362%	2,763
Remaining individualsnot grpmax-eligible	0.016%	6,248
Finnishnot grpmax-eligible	0.00625%	15,988
African / African-American	0.00267%	37,403

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.Ala339Glu
Coding: c.1016C>A
MANE Select: NM_001386140
dbSNP: rs137956833
Type: single nucleotide variant
Location: chr4:99597173 (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 339: the vitellogenin domain

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

Similar variants

MTTP p.Ala339Val Uncertain significance ★★ ⚠ same residue
MTTP p.Ala339= 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

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-ala339glu (accessed [today's date]).

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