Is MGMT p.Pro82Leu (c.245C>T) pathogenic?

MGMT p.Pro82Leu (c.245C>T) is classified Uncertain significance in MGMT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely pathogenic (0.6108); Very rare (popmax 0.00989%, sas).

How common is MGMT p.Pro82Leu (c.245C>T) in the general population?

MGMT p.Pro82Leu (c.245C>T) is very rare (popmax 0.00989%, sas) (gnomAD).

What do computational predictors say about MGMT p.Pro82Leu (c.245C>T)?

AlphaMissense predicts likely pathogenic (score 0.6108) — an in-silico prediction, not a clinical call.

MGMT p.Pro82Leu

c.245C>T · rs761952141 · VCV2236182

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6108 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00989%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6108	likely pathogenic
REVEL	0.356	indeterminate
SaProt	LLR -8.98	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 231 kb · p 0.39 · regional, not allelic
Overall
CADD	27.2	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 0.00989% South Asian · 9/91,046 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.00136% 22/1,613,560 alleles · very rare exomes 18/1,461,350 · genomes 4/152,210 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00989%	10,116
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00267%	37,487
East Asian	0.00223%	44,866
Admixed American	0.00167%	59,928
European (non-Finnish)	0.000593%	168,546

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: MGMT
Protein: p.Pro82Leu
Coding: c.245C>T
MANE Select: NM_002412
dbSNP: rs761952141
Type: single nucleotide variant
Location: chr10:129708014 (GRCh38)
Gene constraint: LOEUF 1.413 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.86 · 23 PDB
Residue 82: an α-helix

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

Similar variants

MGMT p.Glu30Lys Likely benign ★★ same type
MGMT p.Lys178Arg Benign ★★ same type
MGMT c.-54C>G Uncertain significance ★ same type
MGMT c.-60G>T Uncertain significance ★ same type
MGMT p.Ala126Gly Uncertain significance ★ ⚠ same type
MGMT p.Ala197Thr Uncertain significance ★ ⚠ same type
MGMT p.Ala68Thr Uncertain significance ★ ⚠ same type
MGMT p.Ala75Thr 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/mgmt-p-pro82leu (accessed [today's date]).

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