Is PMS2 p.Ser416= (c.1248C>A) pathogenic?

PMS2 p.Ser416= (c.1248C>A) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0333%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

How common is PMS2 p.Ser416= (c.1248C>A) in the general population?

PMS2 p.Ser416= (c.1248C>A) is ultra-rare (popmax 0.0333%, afr) (gnomAD).

PMS2 p.Ser416=

Q: What condition is associated with PMS2 p.Ser416= (c.1248C>A)?

PMS2 p.Ser416= (c.1248C>A) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome, Lynch syndrome 4 (ClinVar).

c.1248C>A · rs780709321 · VCV230291

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, 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 -0.32
Overall
CADD	0.929	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0333% African / African-American · 25/75,048 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00254% 41/1,614,182 alleles · ultra-rare exomes 25/1,461,878 · genomes 16/152,304 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0333%	3,002
Remaining individualsnot grpmax-eligible	0.0112%	8,930
Admixed American	0.00667%	15,002
South Asian	0.0011%	91,084
European (non-Finnish)	0.000339%	295,011

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.Ser416=
Coding: c.1248C>A
MANE Select: NM_000535
dbSNP: rs780709321
Type: single nucleotide variant
Location: chr7:5987517 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 416: 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.Ser416Cys Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser416Phe Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser416Tyr Uncertain significance ★ ⚠ same residue
PMS2 p.Ser416fs Pathogenic ★ 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

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-ser416 (accessed [today's date]).

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