Is SCAF4 p.Pro684Ala (c.2050C>G) pathogenic?

SCAF4 p.Pro684Ala (c.2050C>G) is classified Likely benign in SCAF4 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-12-16). AlphaMissense: likely benign (0.0738); Ultra-rare (popmax 0.0173%, sas); Associated with Inborn genetic diseases.

What condition is associated with SCAF4 p.Pro684Ala (c.2050C>G)?

SCAF4 p.Pro684Ala (c.2050C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SCAF4 p.Pro684Ala (c.2050C>G) in the general population?

SCAF4 p.Pro684Ala (c.2050C>G) is ultra-rare (popmax 0.0173%, sas) (gnomAD).

What do computational predictors say about SCAF4 p.Pro684Ala (c.2050C>G)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

SCAF4 p.Pro684Ala

c.2050C>G · VCV3792887

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -6.68	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 6.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 22 kb · p 2.3e-08 · regional, not allelic
Overall
CADD	23.0	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 0.0173% South Asian · 15/86,740 alleles

Filtering AF 0.0107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0086%

Overall 0.00252% 40/1,590,284 alleles · ultra-rare exomes 29/1,438,006 · genomes 11/152,278 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0173%	5,783
African / African-American	0.0162%	6,172
Admixed American	0.00178%	56,256
European (non-Finnish)	0.00103%	97,540

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: SCAF4
Protein: p.Pro684Ala
Coding: c.2050C>G
MANE Select: NM_020706
Type: single nucleotide variant
Location: chr21:31685727 (GRCh38)
Gene constraint: LOEUF 0.285 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.53 · 1 PDB
Residue 684: a UniProt-annotated variant site (in fzs; likely pathogenic)

Full SCAF4 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

SCAF4 p.Arg71Gln Uncertain significance ★★ ⚠ same condition
SCAF4 p.Asn627Ser Uncertain significance ★★ ⚠ same condition
SCAF4 p.Lys635Glu Uncertain significance ★★ ⚠ same condition
SCAF4 p.Pro330Ala Uncertain significance ★★ ⚠ same condition
SCAF4 p.Ser139Gly Uncertain significance ★★ ⚠ same condition
SCAF4 p.Ser397Ala Uncertain significance ★★ ⚠ same condition
SCAF4 p.Val916Ile Uncertain significance ★★ ⚠ same condition
SCAF4 p.Ile575Val Likely benign ★★ 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/scaf4-p-pro684ala (accessed [today's date]).

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