Is ADGRG2 p.Ser271Phe (c.812C>T) pathogenic?

ADGRG2 p.Ser271Phe (c.812C>T) is classified Uncertain significance in ADGRG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-16). AlphaMissense: likely benign (0.1031); Ultra-rare (popmax 0.0241%, amr); Associated with Inborn genetic diseases.

What condition is associated with ADGRG2 p.Ser271Phe (c.812C>T)?

ADGRG2 p.Ser271Phe (c.812C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ADGRG2 p.Ser271Phe (c.812C>T) in the general population?

ADGRG2 p.Ser271Phe (c.812C>T) is ultra-rare (popmax 0.0241%, amr) (gnomAD).

What do computational predictors say about ADGRG2 p.Ser271Phe (c.812C>T)?

AlphaMissense predicts likely benign (score 0.1031) — an in-silico prediction, not a clinical call.

ADGRG2 p.Ser271Phe

c.812C>T · VCV3836334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1031 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0241%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1031	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -8.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 58 kb · p 0.14 · regional, not allelic
Overall
CADD	20.8	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 0.0241% Admixed American · 11/45,591 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0104%

Overall 0.000993% 12/1,208,393 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0241%	4,145
Remaining individualsnot grpmax-eligible	0.0021%	47,562

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: ADGRG2
Protein: p.Ser271Phe
Coding: c.812C>T
MANE Select: NM_001079858
Type: single nucleotide variant
Location: chrX:19013973 (GRCh38)
Structure: AlphaFold pLDDT 62.76
Residue 271: a UniProt-annotated variant site (in cbavdx; the protein is undetectable); a UniProt-annotated variant site (in cbavdx; uncertain significance)

Full ADGRG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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ADGRG2 p.Arg1008Trp Uncertain significance ★ ⚠ same condition
ADGRG2 p.Arg158Cys Uncertain significance ★ ⚠ same condition
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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/adgrg2-p-ser271phe (accessed [today's date]).

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