Is ADRA2C p.Phe440= (c.1320C>T) pathogenic?

ADRA2C p.Phe440= (c.1320C>T) is classified Likely benign in ADRA2C (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-20). Very rare (popmax 0.000169%, nfe).

How common is ADRA2C p.Phe440= (c.1320C>T) in the general population?

ADRA2C p.Phe440= (c.1320C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

ADRA2C p.Phe440=

c.1320C>T · VCV4966218

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.72, phastCons 1
Overall
CADD	11.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,968 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,459,734 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: ADRA2C
Protein: p.Phe440=
Coding: c.1320C>T
MANE Select: NM_000683
Type: single nucleotide variant
Location: chr4:3767926 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 74.70 · 1 PDB
Residue 440: an α-helix

Full ADRA2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADRA2C p.Ala311= Likely benign ★★ same type
ADRA2C p.Ala115Thr Uncertain significance ★ ⚠ same type
ADRA2C p.Ala16Val Uncertain significance ★ ⚠ same type
ADRA2C p.Ala198Asp Uncertain significance ★ ⚠ same type
ADRA2C p.Ala20Val Uncertain significance ★ ⚠ same type
ADRA2C p.Ala249Gly Uncertain significance ★ ⚠ same type
ADRA2C p.Ala266Val Uncertain significance ★ ⚠ same type
ADRA2C p.Ala268Val 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/adra2c-p-phe440 (accessed [today's date]).

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