Is PMS2 p.His126= (c.378C>T) pathogenic?

PMS2 p.His126= (c.378C>T) is classified Benign/Likely benign in PMS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-01). Very rare (popmax 0.005%, amr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.His126= (c.378C>T)?

PMS2 p.His126= (c.378C>T) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.His126= (c.378C>T) in the general population?

PMS2 p.His126= (c.378C>T) is very rare (popmax 0.005%, amr) (gnomAD).

PMS2 p.His126=

c.378C>T · rs768488890 · VCV187459

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.84 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.046
Overall
CADD	2.574	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,002 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00062% 10/1,611,788 alleles · very rare exomes 10/1,459,466 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,001
East Asian	0.00446%	22,440
African / African-American	0.00267%	37,491
Remaining individualsnot grpmax-eligible	0.0016%	62,310
European (non-Finnish)	0.00017%	589,824

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.His126=
Coding: c.378C>T
MANE Select: NM_000535
dbSNP: rs768488890
Type: single nucleotide variant
Location: chr7:6002612 (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.His126Asp Uncertain significance ★★ ⚠ same residue
PMS2 p.His126Gln Uncertain significance ★★ ⚠ same residue
PMS2 p.His126Tyr 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-his126 (accessed [today's date]).

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