Is MAT2B p.Ala196Pro (c.586G>C) pathogenic?

MAT2B p.Ala196Pro (c.586G>C) is classified Uncertain significance in MAT2B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-05). AlphaMissense: likely pathogenic (0.7538); Ultra-rare (popmax 0.095%, amr).

How common is MAT2B p.Ala196Pro (c.586G>C) in the general population?

MAT2B p.Ala196Pro (c.586G>C) is ultra-rare (popmax 0.095%, amr) (gnomAD).

What do computational predictors say about MAT2B p.Ala196Pro (c.586G>C)?

AlphaMissense predicts likely pathogenic (score 0.7538) — an in-silico prediction, not a clinical call.

MAT2B p.Ala196Pro

c.586G>C · rs201528924 · VCV3123896

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7538 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.095%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7538	likely pathogenic
REVEL	0.446	indeterminate
SaProt	LLR -10.37	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 0.68, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 13 kb · p 0.0009 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.095% Admixed American · 57/60,020 alleles

Filtering AF 0.0752% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.00359% 58/1,614,182 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.095%	1,053
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: MAT2B
Protein: p.Ala196Pro
Coding: c.586G>C
MANE Select: NM_013283
dbSNP: rs201528924
Type: single nucleotide variant
Location: chr5:163516577 (GRCh38)
Gene constraint: LOEUF 0.671 · pLI 0.34 (gnomAD)
Structure: AlphaFold pLDDT 93.82 · 9 PDB

Full MAT2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAT2B p.Ala55Thr Uncertain significance ★ ⚠ same type
MAT2B p.Arg219Lys Uncertain significance ★ ⚠ same type
MAT2B p.Arg289His Uncertain significance ★ ⚠ same type
MAT2B p.Arg30Gly Uncertain significance ★ ⚠ same type
MAT2B p.Arg312Gln Uncertain significance ★ ⚠ same type
MAT2B p.Asn253Ser Uncertain significance ★ ⚠ same type
MAT2B p.Asn270Ser Uncertain significance ★ ⚠ same type
MAT2B p.Asn52Ser 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/mat2b-p-ala196pro (accessed [today's date]).

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