Is SLX4 p.Ser673Phe (c.2018C>T) pathogenic?

SLX4 p.Ser673Phe (c.2018C>T) is classified Uncertain significance in SLX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-22). AlphaMissense: likely benign (0.2761); Very rare (popmax 8.47e-05%, nfe); Associated with Fanconi anemia.

What condition is associated with SLX4 p.Ser673Phe (c.2018C>T)?

SLX4 p.Ser673Phe (c.2018C>T) is associated with Fanconi anemia (ClinVar).

How common is SLX4 p.Ser673Phe (c.2018C>T) in the general population?

SLX4 p.Ser673Phe (c.2018C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Hereditary isolated aplastic anemia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SLX4 p.Ser673Phe (c.2018C>T)?

AlphaMissense predicts likely benign (score 0.2761) — an in-silico prediction, not a clinical call.

SLX4 p.Ser673Phe

c.2018C>T · VCV4746521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2761 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fanconi anemia

Computational evidence

Protein change
AlphaMissense	0.2761	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -6.41	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 5.7	GERP 0.55, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 27 kb · p 0.0005 · regional, not allelic
Overall
CADD	22.3	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 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 0.000186% 3/1,614,092 alleles · very rare exomes 3/1,461,790 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,252
European (non-Finnish)grpmax	8.47e-05%	1,179,997

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SLX4
Protein: p.Ser673Phe
Coding: c.2018C>T
MANE Select: NM_032444
Type: single nucleotide variant
Location: chr16:3594595 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.20 · 7 PDB
Residue 673: an α-helix

Full SLX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Fanconi anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary isolated aplastic anemia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood

Similar variants

SLX4 p.Ser673Cys Uncertain significance ★ ⚠ same residue
SLX4 p.Ser673= Likely benign ★ same residue
SLX4 c.1684-1G>A Likely pathogenic ★★ same condition
SLX4 p.Arg1666Ter Pathogenic/Likely pathogenic ★★ same condition
SLX4 p.Arg481Ter Pathogenic/Likely pathogenic ★★ same condition
SLX4 p.Arg713Ter Pathogenic/Likely pathogenic ★★ same condition
SLX4 p.Gln1201Ter Pathogenic/Likely pathogenic ★★ same condition
SLX4 p.Gln1306Ter Pathogenic ★★ 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/slx4-p-ser673phe (accessed [today's date]).

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