Is PMS2 p.Pro780Thr (c.2338C>A) pathogenic?

PMS2 p.Pro780Thr (c.2338C>A) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.1207); Very rare (popmax 0.0027%, afr); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Pro780Thr (c.2338C>A)?

PMS2 p.Pro780Thr (c.2338C>A) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Pro780Thr (c.2338C>A) in the general population?

PMS2 p.Pro780Thr (c.2338C>A) is very rare (popmax 0.0027%, afr) (gnomAD).

What do computational predictors say about PMS2 p.Pro780Thr (c.2338C>A)?

AlphaMissense predicts likely benign (score 0.1207) — an in-silico prediction, not a clinical call.

PMS2 p.Pro780Thr

c.2338C>A · rs1064796041 · VCV422851

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1207 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0027%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hereditary nonpolyposis colorectal neoplasms

Computational evidence

Protein change
AlphaMissense	0.1207	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -3.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 13 kb · p 2e-20 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0027% African / African-American · 2/74,208 alleles

Filtering AF 0.000447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000187% 3/1,606,286 alleles · very rare exomes 2/1,455,880 · genomes 1/150,406 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0027%	37,104
European (non-Finnish)	8.51e-05%	1,174,914

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.Pro780Thr
Coding: c.2338C>A
MANE Select: NM_000535
dbSNP: rs1064796041
Type: single nucleotide variant
Location: chr7:5977695 (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: hereditary neoplastic syndrome

Similar variants

PMS2 p.Pro780Arg Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro780Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro780Ser Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro780= Likely benign ★★ same residue
PMS2 p.Pro780His Uncertain significance ★ ⚠ same residue
PMS2 p.Pro780fs Pathogenic ★ same residue
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G 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-pro780thr (accessed [today's date]).

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