Is MTTP p.Gln663Arg (c.1988A>G) pathogenic?

MTTP p.Gln663Arg (c.1988A>G) is classified Uncertain significance in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-13). AlphaMissense: ambiguous (0.4321); Very rare (popmax 0.00329%, sas).

How common is MTTP p.Gln663Arg (c.1988A>G) in the general population?

MTTP p.Gln663Arg (c.1988A>G) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about MTTP p.Gln663Arg (c.1988A>G)?

AlphaMissense predicts ambiguous (score 0.4321) — an in-silico prediction, not a clinical call.

MTTP p.Gln663Arg

c.1988A>G · rs754362046 · VCV1422461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4321 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Computational evidence

Protein change
AlphaMissense	0.4321	ambiguous
REVEL	0.519	indeterminate
SaProt	LLR -9.92	tolerated
Splicing
SpliceAI	Δ0.67	donor loss · deltas
Pangolin	Δ0.48	loss · gain 0.03 · agrees with SpliceAI · independent
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	25.5	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 0.00329% South Asian · 3/91,086 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000372% 6/1,614,094 alleles · very rare exomes 6/1,461,734 · genomes 0/152,360 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,362
European (non-Finnish)	0.000254%	393,306

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.Gln663Arg
Coding: c.1988A>G
MANE Select: NM_001386140
dbSNP: rs754362046
Type: single nucleotide variant
Location: chr4:99611452 (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 663: a β-strand

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

Similar variants

MTTP p.Gln663His Uncertain significance ★ ⚠ 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-gln663arg (accessed [today's date]).

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