Is MTTP p.Arg623Cys (c.1867C>T) pathogenic?

MTTP p.Arg623Cys (c.1867C>T) is classified Uncertain significance in MTTP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-16). AlphaMissense: likely benign (0.2189); Ultra-rare (popmax 0.0401%, eas).

How common is MTTP p.Arg623Cys (c.1867C>T) in the general population?

MTTP p.Arg623Cys (c.1867C>T) is ultra-rare (popmax 0.0401%, eas) (gnomAD).

What do computational predictors say about MTTP p.Arg623Cys (c.1867C>T)?

AlphaMissense predicts likely benign (score 0.2189) — an in-silico prediction, not a clinical call.

MTTP p.Arg623Cys

c.1867C>T · rs773117131 · VCV2150087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2189 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2189	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -11.51	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	33.0	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 0.0401% East Asian · 18/44,870 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00236% 38/1,613,026 alleles · ultra-rare exomes 37/1,460,842 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,493
South Asian	0.00879%	11,381
African / African-American	0.00533%	18,749
Admixed American	0.00333%	30,005
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	0.000424%	235,810

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.Arg623Cys
Coding: c.1867C>T
MANE Select: NM_001386140
dbSNP: rs773117131
Type: single nucleotide variant
Location: chr4:99611240 (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 623: the vitellogenin domain; a β-strand

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

Similar variants

MTTP p.Arg623= 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-arg623cys (accessed [today's date]).

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