Is ERCC2 p.Arg616Pro (c.1847G>C) pathogenic?

ERCC2 p.Arg616Pro (c.1847G>C) is classified Pathogenic in ERCC2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-03-25). AlphaMissense: likely pathogenic (0.9993); Ultra-rare (popmax 0.0361%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Arg616Pro (c.1847G>C)?

ERCC2 p.Arg616Pro (c.1847G>C) is associated with Inborn genetic diseases, xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive (ClinVar).

How common is ERCC2 p.Arg616Pro (c.1847G>C) in the general population?

ERCC2 p.Arg616Pro (c.1847G>C) is ultra-rare (popmax 0.0361%, nfe) (gnomAD).

What do computational predictors say about ERCC2 p.Arg616Pro (c.1847G>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg616Pro

c.1847G>C · rs376556895 · VCV329508

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0361%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic ✓ concordant with ClinVar · top 2% in ERCC2
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -17.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	33.0	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 0.0361% European (non-Finnish) · 426/1,179,792 alleles

Filtering AF 0.0332% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0322%

Overall 0.0283% 456/1,613,336 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0361%	2,769
Remaining individualsnot grpmax-eligible	0.0304%	3,287
African / African-American	0.00669%	14,941
Admixed American	0.005%	19,992
Finnishnot grpmax-eligible	0.0047%	21,299

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: ERCC2
Protein: p.Arg616Pro
Coding: c.1847G>C
MANE Select: NM_000400
dbSNP: rs376556895
Type: single nucleotide variant
Location: chr19:45352801 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 616: the 'mediates interaction with mms19' region; a UniProt-annotated variant site (sequence variant); a UniProt-annotated variant site (in xp-d and ttd1); a UniProt-annotated variant site (in xp-d and cofs2)

Full ERCC2 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

Also linked: xeroderma pigmentosum group D trichothiodystrophy 1, photosensitive cerebrooculofacioskeletal syndrome 2 hereditary neoplastic syndrome xeroderma pigmentosum

Similar variants

ERCC2 p.Arg616Trp Pathogenic/Likely pathogenic ★★ same residue
ERCC2 p.Arg616Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ERCC2 p.Arg616fs Pathogenic/Likely pathogenic ★★ same residue
ERCC2 c.1238-1G>C Likely pathogenic ★★ same condition
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1378-1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1479+2T>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1480-1G>C Pathogenic/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/ercc2-p-arg616pro (accessed [today's date]).

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