Is PMS2 p.Asp414= (c.1242C>T) pathogenic?

PMS2 p.Asp414= (c.1242C>T) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.0933%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Asp414= (c.1242C>T) in the general population?

PMS2 p.Asp414= (c.1242C>T) is ultra-rare (popmax 0.0933%, afr) (gnomAD).

PMS2 p.Asp414=

Q: What condition is associated with PMS2 p.Asp414= (c.1242C>T)?

PMS2 p.Asp414= (c.1242C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 4 (ClinVar).

c.1242C>T · rs142839559 · VCV187191

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0933%, afr)

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 -10
Overall
CADD	0.074	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0933% African / African-American · 70/75,044 alleles

Filtering AF 0.0756% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0692%

Overall 0.00558% 90/1,614,148 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0933%	1,072
Middle Eastern	0.0165%	6,062
Admixed American	0.015%	6,667
Remaining individualsnot grpmax-eligible	0.0048%	20,835
East Asian	0.00446%	22,440
European (non-Finnish)	0.000424%	236,005

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.Asp414=
Coding: c.1242C>T
MANE Select: NM_000535
dbSNP: rs142839559
Type: single nucleotide variant
Location: chr7:5987523 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 414: the 'disordered' region

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 Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Asp414Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Asp414His Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Asp414Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Asp414Val Uncertain significance ★ ⚠ same residue
PMS2 p.Asp414fs Pathogenic ★★ same residue
PMS2 p.Asp414Ter Pathogenic ★★ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C 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-asp414 (accessed [today's date]).

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