Is ERCC2 p.Arg616Trp (c.1846C>T) pathogenic?

ERCC2 p.Arg616Trp (c.1846C>T) is classified Pathogenic/Likely pathogenic in ERCC2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-19). AlphaMissense: likely pathogenic (0.9975); Very rare (popmax 0.00878%, sas); Associated with trichothiodystrophy 1, photosensitive.

What condition is associated with ERCC2 p.Arg616Trp (c.1846C>T)?

ERCC2 p.Arg616Trp (c.1846C>T) is associated with trichothiodystrophy 1, photosensitive, xeroderma pigmentosum group D, cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Arg616Trp (c.1846C>T) in the general population?

ERCC2 p.Arg616Trp (c.1846C>T) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about ERCC2 p.Arg616Trp (c.1846C>T)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg616Trp

c.1846C>T · rs121913024 · VCV16788

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

trichothiodystrophy 1, photosensitive

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic ✓ concordant with ClinVar · top 8% in ERCC2
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -17.20	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 5	GERP 0.56, 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 0.00878% South Asian · 8/91,072 alleles

Filtering AF 0.00546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.00626% 101/1,613,504 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,384
African / African-American	0.00802%	12,471
European (non-Finnish)	0.0067%	14,934
Remaining individualsnot grpmax-eligible	0.0064%	15,615
Finnishnot grpmax-eligible	0.00313%	31,951
East Asian	0.00223%	44,870
Admixed American	0.00167%	59,992

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.Arg616Trp
Coding: c.1846C>T
MANE Select: NM_000400
dbSNP: rs121913024
Type: single nucleotide variant
Location: chr19:45352802 (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

trichothiodystrophy 1, photosensitive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group D cerebrooculofacioskeletal syndrome 2 xeroderma pigmentosum

Similar variants

ERCC2 p.Arg616Pro 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-arg616trp (accessed [today's date]).

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