Is MTOR p.Ser338Pro (c.1012T>C) pathogenic?

MTOR p.Ser338Pro (c.1012T>C) is classified Uncertain significance in MTOR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-20). AlphaMissense: likely benign (0.065); Very rare (popmax 0.00446%, eas).

How common is MTOR p.Ser338Pro (c.1012T>C) in the general population?

MTOR p.Ser338Pro (c.1012T>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about MTOR p.Ser338Pro (c.1012T>C)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

MTOR p.Ser338Pro

c.1012T>C · rs761594312 · VCV656599

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -7.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 18 kb · p 7.9e-08 · regional, not allelic
Overall
CADD	22.0	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 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000558% 9/1,613,980 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,443
Admixed American	0.00167%	59,990
African / African-American	0.00134%	74,902
South Asian	0.0011%	91,078
European (non-Finnish)	0.000339%	295,004

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: MTOR
Protein: p.Ser338Pro
Coding: c.1012T>C
MANE Select: NM_004958
dbSNP: rs761594312
Type: single nucleotide variant
Location: chr1:11247923 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.57 · 73 PDB
Residue 338: the 'interaction with nbn' region

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

Similar variants

MTOR p.Ser338Phe Uncertain significance ★ ⚠ same residue
MTOR p.Ser338Cys Benign ★ ⚠ same residue
MTOR p.Ala1669Ser Likely pathogenic ★★★ ⚠ same type
MTOR p.Cys1483Arg Pathogenic ★★★ same type
MTOR p.Cys1483Tyr Pathogenic ★★★ same type
MTOR p.Leu1460Pro Pathogenic ★★★ same type
MTOR p.Leu2427Pro Pathogenic ★★★ same type
MTOR p.Ser2215Phe 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/mtor-p-ser338pro (accessed [today's date]).

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