Is ADRM1 p.Ser223Phe (c.668C>T) pathogenic?

ADRM1 p.Ser223Phe (c.668C>T) is classified Uncertain significance in ADRM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: likely benign (0.1467); Very rare (popmax 0.00668%, eas).

How common is ADRM1 p.Ser223Phe (c.668C>T) in the general population?

ADRM1 p.Ser223Phe (c.668C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about ADRM1 p.Ser223Phe (c.668C>T)?

AlphaMissense predicts likely benign (score 0.1467) — an in-silico prediction, not a clinical call.

ADRM1 p.Ser223Phe

c.668C>T · rs1985276320 · VCV2547717

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1467 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1467	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -12.86	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 5,005 bp · p 0.0094 · regional, not allelic
Overall
CADD	28.7	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 0.00668% East Asian · 3/44,892 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000186% 3/1,612,018 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: ADRM1
Protein: p.Ser223Phe
Coding: c.668C>T
MANE Select: NM_007002
dbSNP: rs1985276320
Type: single nucleotide variant
Location: chr20:62307640 (GRCh38)
Gene constraint: LOEUF 0.188 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.34 · 21 PDB
Residue 223: the 'disordered' region

Full ADRM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADRM1 p.Ala245= Benign ★★ same type
ADRM1 p.Ala324Val Benign ★★ same type
ADRM1 p.Asp266= Benign ★★ same type
ADRM1 p.Pro315= Benign ★★ same type
ADRM1 p.Ala149Gly Uncertain significance ★ ⚠ same type
ADRM1 p.Ala236Thr Uncertain significance ★ ⚠ same type
ADRM1 p.Ala239Thr Uncertain significance ★ ⚠ same type
ADRM1 p.Ala245Thr 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/adrm1-p-ser223phe (accessed [today's date]).

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