Is SALL4 p.Pro433Ser (c.1297C>T) pathogenic?

SALL4 p.Pro433Ser (c.1297C>T) is classified Uncertain significance in SALL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). AlphaMissense: ambiguous (0.5059); Very rare (popmax 0.00133%, afr); Associated with IVIC syndrome.

What condition is associated with SALL4 p.Pro433Ser (c.1297C>T)?

SALL4 p.Pro433Ser (c.1297C>T) is associated with IVIC syndrome, Duane-radial ray syndrome (ClinVar).

How common is SALL4 p.Pro433Ser (c.1297C>T) in the general population?

SALL4 p.Pro433Ser (c.1297C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about SALL4 p.Pro433Ser (c.1297C>T)?

AlphaMissense predicts ambiguous (score 0.5059) — an in-silico prediction, not a clinical call.

SALL4 p.Pro433Ser

c.1297C>T · VCV3587368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5059 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

IVIC syndrome

Computational evidence

Protein change
AlphaMissense	0.5059	ambiguous
REVEL	0.274	benign-leaning
SaProt	LLR -9.44	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 2.4, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 3,245 bp · p 1.1e-08 · regional, not allelic
Overall
CADD	24.6	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 0.00133% African / African-American · 1/74,924 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,032 alleles · very rare exomes 2/1,461,852 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,924
European (non-Finnish)	0.000169%	590,023

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: SALL4
Protein: p.Pro433Ser
Coding: c.1297C>T
MANE Select: NM_020436
Type: single nucleotide variant
Location: chr20:51791186 (GRCh38)
Gene constraint: LOEUF 0.184 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 51.86 · 14 PDB

Full SALL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

IVIC syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Duane-radial ray syndrome

Similar variants

SALL4 p.Arg573Ter Pathogenic ★★ same condition
SALL4 p.Arg831Ter Pathogenic ★★ same condition
SALL4 p.Arg865Ter Pathogenic/Likely pathogenic ★★ same condition
SALL4 c.2743-3T>C Uncertain significance ★★ same condition
SALL4 p.Ala1004Val Uncertain significance ★★ ⚠ same condition
SALL4 p.Ala118Val Uncertain significance ★★ ⚠ same condition
SALL4 p.Ala149Val Uncertain significance ★★ ⚠ same condition
SALL4 p.Ala192Glu 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/sall4-p-pro433ser (accessed [today's date]).

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