Is CD109 p.Phe820Leu (c.2458T>C) pathogenic?

CD109 p.Phe820Leu (c.2458T>C) is classified Uncertain significance in CD109 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-31). AlphaMissense: likely pathogenic (0.8025); Very rare (popmax 0.00167%, amr).

How common is CD109 p.Phe820Leu (c.2458T>C) in the general population?

CD109 p.Phe820Leu (c.2458T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CD109 p.Phe820Leu (c.2458T>C)?

AlphaMissense predicts likely pathogenic (score 0.8025) — an in-silico prediction, not a clinical call.

CD109 p.Phe820Leu

c.2458T>C · rs1774735999 · VCV3140282

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8025 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8025	likely pathogenic · top 6% in CD109
REVEL	0.235	benign-leaning
SaProt	LLR -8.78	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 127 kb · p 0.4 · regional, not allelic
Overall
CADD	25.2	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 0.00167% Admixed American · 1/59,992 alleles

Overall 0.000657% 1/152,204 alleles · very rare

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.Phe820Leu
Coding: c.2458T>C
MANE Select: NM_133493
dbSNP: rs1774735999
Type: single nucleotide variant
Location: chr6:73787354 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.42 · 3 PDB
Residue 820: a β-strand

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

Similar variants

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
CD109 p.Ala1196Val 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-phe820leu (accessed [today's date]).

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