Is ADGRF5 p.Ser896Pro (c.2686T>C) pathogenic?

ADGRF5 p.Ser896Pro (c.2686T>C) is classified Uncertain significance in ADGRF5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-27). AlphaMissense: likely benign (0.2219); Very rare (popmax 0.000339%, nfe).

How common is ADGRF5 p.Ser896Pro (c.2686T>C) in the general population?

ADGRF5 p.Ser896Pro (c.2686T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about ADGRF5 p.Ser896Pro (c.2686T>C)?

AlphaMissense predicts likely benign (score 0.2219) — an in-silico prediction, not a clinical call.

ADGRF5 p.Ser896Pro

c.2686T>C · VCV4638312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2219 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2219	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -10.66	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 6,792 bp · p 8.8e-07 · regional, not allelic
Overall
CADD	16.86	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 0.000339% European (non-Finnish) · 4/1,180,008 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,860 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: ADGRF5
Protein: p.Ser896Pro
Coding: c.2686T>C
MANE Select: NM_001098518
Type: single nucleotide variant
Location: chr6:46859217 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.74
Residue 896: the gain-b domain

Full ADGRF5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRF5 p.Ser896Ala Uncertain significance ★ ⚠ same residue
ADGRF5 p.Ala1064Val Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala1072Thr Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala1072Val Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala1088Ser Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala1179Glu Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala268Thr Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala324Val 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/adgrf5-p-ser896pro (accessed [today's date]).

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