Is PMS2 p.Leu718Phe (c.2152C>T) pathogenic?

PMS2 p.Leu718Phe (c.2152C>T) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-27). AlphaMissense: ambiguous (0.5052); Very rare (popmax 0.00135%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Leu718Phe (c.2152C>T)?

PMS2 p.Leu718Phe (c.2152C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Leu718Phe (c.2152C>T) in the general population?

PMS2 p.Leu718Phe (c.2152C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about PMS2 p.Leu718Phe (c.2152C>T)?

AlphaMissense predicts ambiguous (score 0.5052) — an in-silico prediction, not a clinical call.

PMS2 p.Leu718Phe

c.2152C>T · rs139765160 · VCV455686

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5052 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.5052	ambiguous
REVEL	0.51	indeterminate
SaProt	LLR -8.12	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 13 kb · p 2e-20 · regional, not allelic
Overall
CADD	22.0	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 0.00135% African / African-American · 1/74,258 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000373% 6/1,608,834 alleles · very rare exomes 5/1,457,200 · genomes 1/151,634 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,258
European (non-Finnish)	0.000424%	235,661

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: PMS2
Protein: p.Leu718Phe
Coding: c.2152C>T
MANE Select: NM_000535
dbSNP: rs139765160
Type: single nucleotide variant
Location: chr7:5982846 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hereditary nonpolyposis colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Leu718Pro Uncertain significance ★★ ⚠ same residue
PMS2 p.Leu718= Benign/Likely benign ★★ same residue
PMS2 p.Leu718Ile Uncertain significance ★ ⚠ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G Likely pathogenic ★★★ same condition
PMS2 c.2007-1G>A Likely pathogenic ★★★ same condition
PMS2 c.2174+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/pms2-p-leu718phe (accessed [today's date]).

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