Is CROCC p.Ser1696Arg (c.5088C>G) pathogenic?

CROCC p.Ser1696Arg (c.5088C>G) is classified Uncertain significance in CROCC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely pathogenic (0.5756); Ultra-rare (popmax 0.0135%, eas).

How common is CROCC p.Ser1696Arg (c.5088C>G) in the general population?

CROCC p.Ser1696Arg (c.5088C>G) is ultra-rare (popmax 0.0135%, eas) (gnomAD).

What do computational predictors say about CROCC p.Ser1696Arg (c.5088C>G)?

AlphaMissense predicts likely pathogenic (score 0.5756) — an in-silico prediction, not a clinical call.

CROCC p.Ser1696Arg

c.5088C>G · VCV3497234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5756 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5756	likely pathogenic · top 9% in CROCC
REVEL	0.389	indeterminate
SaProt	LLR -7.46	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.5	GERP -2.8
Regional constraint	o/e 0.95	unconstrained · MANE · 18 kb · p 0.057 · regional, not allelic
Overall
CADD	6.823	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 0.0135% East Asian · 6/44,466 alleles

Filtering AF 0.00583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00397%

Overall 0.000562% 9/1,602,106 alleles · ultra-rare exomes 6/1,449,770 · genomes 3/152,336 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0135%	7,411
Admixed American	0.00521%	19,181

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: CROCC
Protein: p.Ser1696Arg
Coding: c.5088C>G
MANE Select: NM_014675
Type: single nucleotide variant
Location: chr1:16969127 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 2 PDB

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

Similar variants

CROCC p.Arg1094Trp Uncertain significance ★★ ⚠ same type
CROCC p.Asp1119His Uncertain significance ★★ ⚠ same type
CROCC p.Gly486Arg Uncertain significance ★★ ⚠ same type
CROCC p.Arg1729Gln Likely benign ★★ same type
CROCC p.Arg1908Cys Benign ★★ ⚠ same type
CROCC p.Arg675His Benign ★★ same type
CROCC p.Arg691His Benign ★★ same type
CROCC p.Arg903Ser Benign/Likely benign ★★ same type

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/crocc-p-ser1696arg (accessed [today's date]).

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