Is MTTP p.Arg626His (c.1877G>A) pathogenic?

MTTP p.Arg626His (c.1877G>A) is classified Uncertain significance in MTTP (ClinVar, Single submitter, 3 submitters; last evaluated 2022-10-25). AlphaMissense: likely benign (0.0593); Ultra-rare (popmax 0.0867%, sas).

How common is MTTP p.Arg626His (c.1877G>A) in the general population?

MTTP p.Arg626His (c.1877G>A) is ultra-rare (popmax 0.0867%, sas) (gnomAD).

What do computational predictors say about MTTP p.Arg626His (c.1877G>A)?

AlphaMissense predicts likely benign (score 0.0593) — an in-silico prediction, not a clinical call.

MTTP p.Arg626His

c.1877G>A · rs568076672 · VCV1299919

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0593 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0867%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0593	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -3.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.37	GERP -3
Regional constraint	o/e 0.89	unconstrained · MANE · 48 kb · p 0.00018 · regional, not allelic
Overall
CADD	7.464	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0867% South Asian · 79/91,084 alleles

Filtering AF 0.0713% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0656%

Overall 0.00564% 91/1,613,974 alleles · ultra-rare exomes 87/1,461,790 · genomes 4/152,184 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0867%	1,153
Remaining individualsnot grpmax-eligible	0.0048%	20,834
East Asian	0.00223%	44,880
Admixed American	0.00167%	60,012
European (non-Finnish)	0.000593%	168,560

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.Arg626His
Coding: c.1877G>A
MANE Select: NM_001386140
dbSNP: rs568076672
Type: single nucleotide variant
Location: chr4:99611341 (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 626: the vitellogenin domain; a β-strand

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

Similar variants

MTTP p.Arg626Cys 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-arg626his (accessed [today's date]).

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