Is ADGRD1 p.Ser577Phe (c.1730C>T) pathogenic?

ADGRD1 p.Ser577Phe (c.1730C>T) is classified Uncertain significance in ADGRD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.9848); Very rare (popmax 0.00288%, nfe).

How common is ADGRD1 p.Ser577Phe (c.1730C>T) in the general population?

ADGRD1 p.Ser577Phe (c.1730C>T) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about ADGRD1 p.Ser577Phe (c.1730C>T)?

AlphaMissense predicts likely pathogenic (score 0.9848) — an in-silico prediction, not a clinical call.

ADGRD1 p.Ser577Phe

c.1730C>T · VCV4832782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9848	likely pathogenic · top 2% in ADGRD1
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -16.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 185 kb · p 0.0023 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00288% European (non-Finnish) · 33/1,147,274 alleles

Filtering AF 0.00205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00219% 34/1,551,422 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,766
Admixed American	0.00196%	51,092

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: ADGRD1
Protein: p.Ser577Phe
Coding: c.1730C>T
MANE Select: NM_198827
Type: single nucleotide variant
Location: chr12:131104889 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 8 PDB
Residue 577: an α-helix

Full ADGRD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/adgrd1-p-ser577phe (accessed [today's date]).

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