Is SCAF4 p.Pro754Ser (c.2260C>T) pathogenic?

SCAF4 p.Pro754Ser (c.2260C>T) is classified Uncertain significance in SCAF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-10). AlphaMissense: ambiguous (0.4306); Very rare (popmax 8.48e-05%, nfe).

How common is SCAF4 p.Pro754Ser (c.2260C>T) in the general population?

SCAF4 p.Pro754Ser (c.2260C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SCAF4 p.Pro754Ser (c.2260C>T)?

AlphaMissense predicts ambiguous (score 0.4306) — an in-silico prediction, not a clinical call.

SCAF4 p.Pro754Ser

c.2260C>T · VCV4057132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4306 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4306	ambiguous
REVEL	0.251	benign-leaning
SaProt	LLR -9.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 22 kb · p 2.3e-08 · regional, not allelic
Overall
CADD	22.9	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 8.48e-05% European (non-Finnish) · 1/1,179,674 alleles

Overall 6.2e-05% 1/1,613,494 alleles · very rare exomes 1/1,461,222 · genomes 0/152,272 · joint denominator

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.Pro754Ser
Coding: c.2260C>T
MANE Select: NM_020706
Type: single nucleotide variant
Location: chr21:31685434 (GRCh38)
Gene constraint: LOEUF 0.285 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.53 · 1 PDB
Residue 754: a UniProt-annotated variant site (in fzs; likely pathogenic)

Full SCAF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SCAF4 p.Arg447Ter Pathogenic ★★ same type
SCAF4 p.Arg475Ter Pathogenic ★★ same type
SCAF4 p.Arg477Ter Pathogenic ★★ same type
SCAF4 p.Arg491Ter Pathogenic/Likely pathogenic ★★ same type
SOD1 p.Gly73Ser Likely pathogenic ★★ same type
SCAF4 p.Arg71Gln Uncertain significance ★★ ⚠ same type
SCAF4 p.Asn627Ser Uncertain significance ★★ ⚠ same type
SCAF4 p.Lys635Glu 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/scaf4-p-pro754ser (accessed [today's date]).

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