Is CNOT3 p.Pro314Ser (c.940C>T) pathogenic?

CNOT3 p.Pro314Ser (c.940C>T) is classified Benign in CNOT3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0576); Rare (popmax 0.714%, mid).

How common is CNOT3 p.Pro314Ser (c.940C>T) in the general population?

CNOT3 p.Pro314Ser (c.940C>T) is rare (popmax 0.714%, mid) (gnomAD).

What do computational predictors say about CNOT3 p.Pro314Ser (c.940C>T)?

AlphaMissense predicts likely benign (score 0.0576) — an in-silico prediction, not a clinical call.

CNOT3 p.Pro314Ser

c.940C>T · rs138658963 · VCV1657489

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0576 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.714%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0576	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -5.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.13, phastCons 0.98
Regional constraint	o/e 0.96	unconstrained · MANE · 7,004 bp · p 0.37 · regional, not allelic
Overall
CADD	18.84	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.714% Middle Eastern · 42/5,886 alleles

Filtering AF 0.584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.58%

Overall 0.503% 7,906/1,573,124 alleles · rare exomes 7,415/1,420,856 · genomes 491/152,268 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.1%	91
Middle Easterngrpmax	0.714%	140
European (non-Finnish)	0.596%	168
Ashkenazi Jewishnot grpmax-eligible	0.532%	188
Remaining individualsnot grpmax-eligible	0.451%	222
South Asian	0.365%	274
Admixed American	0.176%	567
African / African-American	0.113%	886
Finnishnot grpmax-eligible	0.0421%	2,373
East Asian	0.00229%	43,600

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CNOT3
Protein: p.Pro314Ser
Coding: c.940C>T
MANE Select: NM_014516
dbSNP: rs138658963
Type: single nucleotide variant
Location: chr19:54148193 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB
Residue 314: the 'disordered' region

Full CNOT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT3 p.Pro314fs Likely pathogenic ★ same residue
CNOT3 c.1904+2T>C Pathogenic/Likely pathogenic ★★ same type
CNOT3 p.Arg697Ter Pathogenic ★★ same type
CNOT3 p.Arg81Ser Likely pathogenic ★★ same type
CNOT3 p.Arg96Ter Pathogenic/Likely pathogenic ★★ same type
CNOT3 p.Thr86= Likely pathogenic ★★ same type
CNOT3 c.1905-7C>G Uncertain significance ★★ same type
CNOT3 c.483+6T>G Uncertain significance ★★ same type

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/cnot3-p-pro314ser (accessed [today's date]).

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