Is ERCC4 p.Arg576Ser (c.1728A>T) pathogenic?

ERCC4 p.Arg576Ser (c.1728A>T) is classified Uncertain significance in ERCC4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-05-15). AlphaMissense: ambiguous (0.549); Very rare (popmax 0.00924%, nfe); Associated with xeroderma pigmentosum group F.

What condition is associated with ERCC4 p.Arg576Ser (c.1728A>T)?

ERCC4 p.Arg576Ser (c.1728A>T) is associated with xeroderma pigmentosum group F, XFE progeroid syndrome, Fanconi anemia complementation group Q (ClinVar).

How common is ERCC4 p.Arg576Ser (c.1728A>T) in the general population?

ERCC4 p.Arg576Ser (c.1728A>T) is very rare (popmax 0.00924%, nfe) (gnomAD).

What do computational predictors say about ERCC4 p.Arg576Ser (c.1728A>T)?

AlphaMissense predicts ambiguous (score 0.549) — an in-silico prediction, not a clinical call.

ERCC4 p.Arg576Ser

Q: How is Xeroderma pigmentosum-Cockayne syndrome complex inherited?

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

c.1728A>T · rs765454246 · VCV317816

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.549 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00924%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

xeroderma pigmentosum group F

Computational evidence

Protein change
AlphaMissense	0.549	ambiguous
REVEL	0.093	moderately benign-leaning
SaProt	LLR -4.95	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ1.00 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.5	GERP -2.6, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 28 kb · p 0.011 · regional, not allelic
Overall
CADD	18.58	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 0.00924% European (non-Finnish) · 109/1,180,014 alleles

Filtering AF 0.00782% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00727%

Overall 0.00756% 122/1,614,018 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0141%	7,116
European (non-Finnish)grpmax	0.00924%	10,826
Remaining individualsnot grpmax-eligible	0.0032%	31,243
Admixed American	0.00167%	59,990
African / African-American	0.00133%	74,912

Finnish 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: ERCC4
Protein: p.Arg576Ser
Coding: c.1728A>T
MANE Select: NM_005236
dbSNP: rs765454246
Type: single nucleotide variant
Location: chr16:13935660 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.60 · 13 PDB
Residue 576: a UniProt-annotated variant site (in)

Full ERCC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

xeroderma pigmentosum group F — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: XFE progeroid syndrome Fanconi anemia complementation group Q Cockayne syndrome

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC4 p.Arg576Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
ERCC4 p.Arg576= Likely benign ★ same residue
ERCC4 p.Arg576_Tyr577insTer Pathogenic ★ same residue
ERCC4 c.1102+1G>T Likely pathogenic ★★ same condition
ERCC4 c.793-2A>G Pathogenic ★★ same condition
ERCC4 p.Arg20Ter Pathogenic ★★ same condition
ERCC4 p.Arg589Trp Pathogenic/Likely pathogenic ★★ same condition
ERCC4 p.Arg689Ser Likely 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/ercc4-p-arg576ser (accessed [today's date]).

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