Is CD109 p.Gly489Ser (c.1465G>A) pathogenic?

CD109 p.Gly489Ser (c.1465G>A) is classified Uncertain significance in CD109 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.0866); Low-frequency (popmax 1.01%, afr).

How common is CD109 p.Gly489Ser (c.1465G>A) in the general population?

CD109 p.Gly489Ser (c.1465G>A) is low-frequency (popmax 1.01%, afr) (gnomAD).

What do computational predictors say about CD109 p.Gly489Ser (c.1465G>A)?

AlphaMissense predicts likely benign (score 0.0866) — an in-silico prediction, not a clinical call.

CD109 p.Gly489Ser

c.1465G>A · VCV4222526

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0866 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.01%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0866	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -3.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	donor loss, 32 bp away · masked 0 · deltas
Pangolin	Δ0.20	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2	GERP 0.01, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 127 kb · p 0.4 · regional, not allelic
Overall
CADD	9.587	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 1.01% African / African-American · 755/74,818 alleles

Filtering AF 0.949% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.926%

Overall 0.0641% 1,034/1,613,006 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.01%	99
Remaining individualsnot grpmax-eligible	0.0993%	1,007
Middle Eastern	0.0831%	1,204
Admixed American	0.0667%	1,499
European (non-Finnish)	0.0143%	6,980
South Asian	0.0033%	30,315

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: CD109
Protein: p.Gly489Ser
Coding: c.1465G>A
MANE Select: NM_133493
Type: single nucleotide variant
Location: chr6:73766978 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.42 · 3 PDB
Residue 489: a β-strand

Full CD109 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD109 p.Gly489Asp Uncertain significance ★ ⚠ same residue
CD109 p.Gln416Glu Likely benign ★★ same type
CD109 p.Ile206Val Benign ★★ ⚠ same type
CD109 p.Ala1104Val Uncertain significance ★ ⚠ same type
CD109 p.Ala1115Gly Uncertain significance ★ ⚠ same type
CD109 p.Ala1148Gly Uncertain significance ★ ⚠ same type
CD109 p.Ala1190Pro Uncertain significance ★ ⚠ same type
CD109 p.Ala1196Asp 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/cd109-p-gly489ser (accessed [today's date]).

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