Is SCARF2 p.Pro657Ser (c.1969C>T) pathogenic?

SCARF2 p.Pro657Ser (c.1969C>T) is classified Uncertain significance in SCARF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: likely pathogenic (0.7853); Very rare (popmax 0.00139%, afr); Associated with Inborn genetic diseases.

What condition is associated with SCARF2 p.Pro657Ser (c.1969C>T)?

SCARF2 p.Pro657Ser (c.1969C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SCARF2 p.Pro657Ser (c.1969C>T) in the general population?

SCARF2 p.Pro657Ser (c.1969C>T) is very rare (popmax 0.00139%, afr) (gnomAD).

What do computational predictors say about SCARF2 p.Pro657Ser (c.1969C>T)?

AlphaMissense predicts likely pathogenic (score 0.7853) — an in-silico prediction, not a clinical call.

SCARF2 p.Pro657Ser

c.1969C>T · rs369044776 · VCV2464359

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00139%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7853	likely pathogenic
REVEL	0.159	moderately benign-leaning
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.94, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 3,952 bp · p 0.87 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P662S vs ClinVar P657S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00139% African / African-American · 1/71,772 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000253% 4/1,582,900 alleles · very rare exomes 2/1,430,910 · genomes 2/151,990 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00139%	71,772
European (non-Finnish)	0.000256%	390,562

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: SCARF2
Protein: p.Pro657Ser
Coding: c.1969C>T
MANE Select: NM_182895
dbSNP: rs369044776
Type: single nucleotide variant
Location: chr22:20426007 (GRCh38)
Gene constraint: LOEUF 0.992 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.63
Residue 662 UniProt numbering: the 'disordered' region

Full SCARF2 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

SCARF2 p.Pro657Arg Uncertain significance ★ ⚠ same residue
SCARF2 p.Ala12Ser Uncertain significance ★★ ⚠ same condition
SCARF2 p.Ala627Val Uncertain significance ★★ ⚠ same condition
SCARF2 p.Ala854Thr Uncertain significance ★★ ⚠ same condition
SCARF2 p.Arg860Lys Uncertain significance ★★ ⚠ same condition
SCARF2 p.Asp378Glu Uncertain significance ★★ ⚠ same condition
SCARF2 p.Asp830Asn Uncertain significance ★★ ⚠ same condition
SCARF2 p.Glu581Gln Uncertain significance ★★ ⚠ same condition

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/scarf2-p-pro657ser (accessed [today's date]).

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