Is ADGRG3 p.Phe371Ser (c.1112T>C) pathogenic?

ADGRG3 p.Phe371Ser (c.1112T>C) is classified Uncertain significance in ADGRG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely pathogenic (0.701); Very rare (popmax 0.00669%, eas).

How common is ADGRG3 p.Phe371Ser (c.1112T>C) in the general population?

ADGRG3 p.Phe371Ser (c.1112T>C) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about ADGRG3 p.Phe371Ser (c.1112T>C)?

AlphaMissense predicts likely pathogenic (score 0.701) — an in-silico prediction, not a clinical call.

ADGRG3 p.Phe371Ser

c.1112T>C · VCV4240907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.701	likely pathogenic
REVEL	0.581	indeterminate
SaProt	LLR -11.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.12 · regional, not allelic
Overall
CADD	26.3	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 0.00669% East Asian · 3/44,876 alleles

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

Overall 0.000274% 4/1,461,744 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,959
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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: ADGRG3
Protein: p.Phe371Ser
Coding: c.1112T>C
MANE Select: NM_170776
Type: single nucleotide variant
Location: chr16:57684162 (GRCh38)
Gene constraint: LOEUF 0.93 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.48 · 3 PDB
Residue 371: a disulfide bond

Full ADGRG3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRG3 p.Ala253Thr Uncertain significance ★ ⚠ same type
ADGRG3 p.Ala311Val Uncertain significance ★ ⚠ same type
ADGRG3 p.Ala543Ser Uncertain significance ★ ⚠ same type
ADGRG3 p.Ala546Thr Uncertain significance ★ ⚠ same type
ADGRG3 p.Ala9Pro Uncertain significance ★ ⚠ same type
ADGRG3 p.Arg139Gln Uncertain significance ★ ⚠ same type
ADGRG3 p.Arg149His Uncertain significance ★ ⚠ same type
ADGRG3 p.Arg180Cys 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/adgrg3-p-phe371ser (accessed [today's date]).

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