Is PMS2 p.Phe506= (c.1518C>T) pathogenic?

PMS2 p.Phe506= (c.1518C>T) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-02). Very rare (popmax 0.00133%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Phe506= (c.1518C>T)?

PMS2 p.Phe506= (c.1518C>T) is associated with hereditary neoplastic syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Phe506= (c.1518C>T) in the general population?

PMS2 p.Phe506= (c.1518C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

PMS2 p.Phe506=

c.1518C>T · rs1554297654 · VCV484273

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, 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 2.2	phastCons 0.19
Overall
CADD	6.496	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,018 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00062% 10/1,614,052 alleles · very rare exomes 10/1,461,822 · genomes 0/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,018
European (non-Finnish)	0.000763%	131,113

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.Phe506=
Coding: c.1518C>T
MANE Select: NM_000535
dbSNP: rs1554297654
Type: single nucleotide variant
Location: chr7:5987247 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 506: the 'disordered' region

Full PMS2 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: Lynch syndrome 4

Similar variants

PMS2 p.Phe506Cys Uncertain significance ★★ ⚠ same residue
PMS2 p.Phe506fs Pathogenic ★★ same residue
PMS2 p.Phe506Tyr 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-phe506 (accessed [today's date]).

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