Is MTCH2 p.Arg185His (c.554G>A) pathogenic?

MTCH2 p.Arg185His (c.554G>A) is classified Uncertain significance in MTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely pathogenic (0.7618); Very rare (popmax 0.00223%, eas).

How common is MTCH2 p.Arg185His (c.554G>A) in the general population?

MTCH2 p.Arg185His (c.554G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MTCH2 p.Arg185His (c.554G>A)?

AlphaMissense predicts likely pathogenic (score 0.7618) — an in-silico prediction, not a clinical call.

MTCH2 p.Arg185His

c.554G>A · VCV3914016

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7618	likely pathogenic
REVEL	0.531	indeterminate
SaProt	LLR -4.96	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.43 · evaluated, not missing
Pangolin	Δ0.22	loss · gain 0.05 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 13 kb · p 0.0083 · regional, not allelic
Overall
CADD	24.2	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 0.00223% East Asian · 1/44,856 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00093% 15/1,612,894 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,856
Remaining individualsnot grpmax-eligible	0.0016%	62,446
European (non-Finnish)	0.0011%	90,744

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: MTCH2
Protein: p.Arg185His
Coding: c.554G>A
MANE Select: NM_014342
Type: single nucleotide variant
Location: chr11:47629032 (GRCh38)
Gene constraint: LOEUF 0.751 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.47 · 3 PDB

Full MTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTCH2 p.Ile16Leu Uncertain significance ★★ ⚠ same type
MTCH2 p.Ala180Thr Uncertain significance ★ ⚠ same type
MTCH2 p.Ala224Thr Uncertain significance ★ ⚠ same type
MTCH2 p.Arg131Cys Uncertain significance ★ ⚠ same type
MTCH2 p.Arg131His Uncertain significance ★ ⚠ same type
MTCH2 p.Arg155Lys Uncertain significance ★ ⚠ same type
MTCH2 p.Arg171Trp Uncertain significance ★ ⚠ same type
MTCH2 p.Arg287Trp 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/mtch2-p-arg185his (accessed [today's date]).

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