Is CEACAM8 p.Pro220Ser (c.658C>T) pathogenic?

CEACAM8 p.Pro220Ser (c.658C>T) is classified Uncertain significance in CEACAM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.1096); Very rare (popmax 0.00439%, sas).

How common is CEACAM8 p.Pro220Ser (c.658C>T) in the general population?

CEACAM8 p.Pro220Ser (c.658C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about CEACAM8 p.Pro220Ser (c.658C>T)?

AlphaMissense predicts likely benign (score 0.1096) — an in-silico prediction, not a clinical call.

CEACAM8 p.Pro220Ser

c.658C>T · VCV4225018

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1096 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1096	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -8.66	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 -0.12	GERP -0.6
Regional constraint	o/e 0.89	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	9.868	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 0.00439% South Asian · 4/91,082 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00124% 20/1,614,096 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
Admixed American	0.00167%	60,014
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.00119%	84,289

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: CEACAM8
Protein: p.Pro220Ser
Coding: c.658C>T
MANE Select: NM_001816
Type: single nucleotide variant
Location: chr19:42589502 (GRCh38)
Gene constraint: LOEUF 1.219 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.26 · 4 PDB
Residue 220: the ig-like c2-type 1 domain

Full CEACAM8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CEACAM8 p.Pro220Arg Uncertain significance ★ ⚠ same residue
CEACAM8 p.Pro186Leu Uncertain significance ★★ ⚠ same type
CEACAM8 p.Ala162Val Uncertain significance ★ ⚠ same type
CEACAM8 p.Ala261Glu Uncertain significance ★ ⚠ same type
CEACAM8 p.Ala321Val Uncertain significance ★ ⚠ same type
CEACAM8 p.Arg10Lys Uncertain significance ★ ⚠ same type
CEACAM8 p.Arg345Lys Uncertain significance ★ ⚠ same type
CEACAM8 p.Arg345Met 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/ceacam8-p-pro220ser (accessed [today's date]).

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