Is PTEN p.Pro246= (c.738G>A) pathogenic?

PTEN p.Pro246= (c.738G>A) is classified Benign/Likely benign in PTEN (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-10-14). Very rare (popmax 0.00667%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with PTEN p.Pro246= (c.738G>A)?

PTEN p.Pro246= (c.738G>A) is associated with hereditary neoplastic syndrome, Cowden syndrome 1, PTEN hamartoma tumor syndrome (ClinVar).

How common is PTEN p.Pro246= (c.738G>A) in the general population?

PTEN p.Pro246= (c.738G>A) is very rare (popmax 0.00667%, afr) (gnomAD).

PTEN p.Pro246=

c.738G>A · rs774364894 · VCV215734

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5	GERP -4.9
Overall
CADD	2.568	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,920 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000867% 14/1,613,926 alleles · very rare exomes 12/1,461,782 · genomes 2/152,144 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,984
Admixed American	0.005%	19,999
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
South Asian	0.0011%	91,090
European (non-Finnish)	0.000339%	294,990

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: PTEN
Protein: p.Pro246=
Coding: c.738G>A
MANE Select: NM_000314
dbSNP: rs774364894
Type: single nucleotide variant
Location: chr10:87957956 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 246: a β-strand; the c2 tensin-type domain; a UniProt-annotated variant site (in mcephas); a UniProt-annotated variant site (in cws1)

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cowden syndrome 1 PTEN hamartoma tumor syndrome

Similar variants

PTEN p.Pro246Leu Pathogenic ★★★ same residue
PTEN p.Pro246Gln Uncertain significance ★★ ⚠ same residue
PTEN p.Pro246Arg Uncertain significance ★ ⚠ same residue
PTEN p.Pro246Thr Uncertain significance ★ ⚠ same residue
PTEN p.Pro246fs Pathogenic ★ same residue
PTEN c.1026+1G>A Pathogenic ★★★ same condition
PTEN c.1027-1852A>G Likely pathogenic ★★★ same condition
PTEN c.1027-1G>A Pathogenic ★★★ same condition

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/pten-p-pro246 (accessed [today's date]).

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