Is MTREX p.Ser622Arg (c.1864A>C) pathogenic?

MTREX p.Ser622Arg (c.1864A>C) is classified Uncertain significance in MTREX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: likely pathogenic (0.7823); Very rare (popmax 0.00402%, afr).

How common is MTREX p.Ser622Arg (c.1864A>C) in the general population?

MTREX p.Ser622Arg (c.1864A>C) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about MTREX p.Ser622Arg (c.1864A>C)?

AlphaMissense predicts likely pathogenic (score 0.7823) — an in-silico prediction, not a clinical call.

MTREX p.Ser622Arg

c.1864A>C · VCV3914436

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7823 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7823	likely pathogenic
REVEL	0.124	moderately benign-leaning
SaProt	LLR -8.73	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 66 kb · p 4.4e-07 · regional, not allelic
Overall
CADD	22.5	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 0.00402% African / African-American · 3/74,704 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000186% 3/1,609,552 alleles · very rare exomes 1/1,457,308 · genomes 2/152,244 · joint denominator

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: MTREX
Protein: p.Ser622Arg
Coding: c.1864A>C
MANE Select: NM_015360
Type: single nucleotide variant
Location: chr5:55378367 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 84.68 · 11 PDB

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

Similar variants

MTREX p.Ala247Pro Uncertain significance ★ ⚠ same type
MTREX p.Ala93Thr Uncertain significance ★ ⚠ same type
MTREX p.Ala974Thr Uncertain significance ★ ⚠ same type
MTREX p.Arg128Gln Uncertain significance ★ ⚠ same type
MTREX p.Arg184Cys Uncertain significance ★ ⚠ same type
MTREX p.Arg290Gln Uncertain significance ★ ⚠ same type
MTREX p.Arg364Gln Uncertain significance ★ ⚠ same type
MTREX p.Arg364Trp Uncertain significance ★ ⚠ 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/mtrex-p-ser622arg (accessed [today's date]).

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