Is PMS2 p.Phe709= (c.2127C>T) pathogenic?

PMS2 p.Phe709= (c.2127C>T) is classified Conflicting classifications of pathogenicity in PMS2 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.0223%, eas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Phe709= (c.2127C>T)?

PMS2 p.Phe709= (c.2127C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Phe709= (c.2127C>T) in the general population?

PMS2 p.Phe709= (c.2127C>T) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

PMS2 p.Phe709=

c.2127C>T · rs199943748 · VCV194001

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Conditions

Hereditary nonpolyposis colorectal neoplasms

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
Overall
CADD	0.586	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0223% East Asian · 10/44,814 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00918%

Overall 0.00578% 93/1,607,652 alleles · ultra-rare exomes 79/1,455,992 · genomes 14/151,660 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,481
African / African-American	0.0108%	9,294
South Asian	0.00552%	18,112
European (non-Finnish)	0.00552%	18,112
Finnishnot grpmax-eligible	0.00469%	21,308
Admixed American	0.00336%	29,760

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.Phe709=
Coding: c.2127C>T
MANE Select: NM_000535
dbSNP: rs199943748
Type: single nucleotide variant
Location: chr7:5982871 (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.Phe709Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Phe709Ser 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
PMS2 c.705+1G>T Likely 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-phe709 (accessed [today's date]).

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