Is ADGRF5 p.Ser838Pro (c.2512T>C) pathogenic?

ADGRF5 p.Ser838Pro (c.2512T>C) is classified Uncertain significance in ADGRF5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-19). AlphaMissense: likely benign (0.0632); Ultra-rare (popmax 0.0365%, nfe).

How common is ADGRF5 p.Ser838Pro (c.2512T>C) in the general population?

ADGRF5 p.Ser838Pro (c.2512T>C) is ultra-rare (popmax 0.0365%, nfe) (gnomAD).

What do computational predictors say about ADGRF5 p.Ser838Pro (c.2512T>C)?

AlphaMissense predicts likely benign (score 0.0632) — an in-silico prediction, not a clinical call.

ADGRF5 p.Ser838Pro

c.2512T>C · VCV3271454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0632 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0365%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0632	likely benign
REVEL	0.004	strongly benign-leaning
SaProt	LLR -6.01	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 -0.91	GERP -3.6
Regional constraint	o/e 0.81	unconstrained · MANE · 6,792 bp · p 8.8e-07 · regional, not allelic
Overall
CADD	0.022	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 0.0365% European (non-Finnish) · 431/1,179,472 alleles

Filtering AF 0.0337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.0282% 455/1,613,394 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0365%	2,737
Remaining individualsnot grpmax-eligible	0.0272%	3,674
African / African-American	0.00534%	18,728
Admixed American	0.00333%	29,995
South Asian	0.0011%	91,060

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.Ser838Pro
Coding: c.2512T>C
MANE Select: NM_001098518
Type: single nucleotide variant
Location: chr6:46859391 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.74

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

Similar variants

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
ADGRF5 p.Ala457Thr 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-ser838pro (accessed [today's date]).

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