Is C2CD3 p.His240Asp (c.718C>G) pathogenic?

C2CD3 p.His240Asp (c.718C>G) is classified Benign in C2CD3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1389); Low-frequency (popmax 1.94%, nfe).

How common is C2CD3 p.His240Asp (c.718C>G) in the general population?

C2CD3 p.His240Asp (c.718C>G) is low-frequency (popmax 1.94%, nfe) (gnomAD).

What do computational predictors say about C2CD3 p.His240Asp (c.718C>G)?

AlphaMissense predicts likely benign (score 0.1389) — an in-silico prediction, not a clinical call.

C2CD3 p.His240Asp

c.718C>G · rs72984881 · VCV1552249

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1389 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.94%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1389	likely benign
REVEL	0.166	moderately benign-leaning
SaProt	LLR -6.78	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 7.6	GERP 0.91, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 157 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	22.5	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 1.94% European (non-Finnish) · 22,854/1,175,262 alleles

Filtering AF 1.92% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.91%

Overall 1.63% 26,256/1,607,050 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.34%	43
European (non-Finnish)grpmax	1.94%	51
Remaining individualsnot grpmax-eligible	1.49%	67
Admixed American	0.681%	147
Ashkenazi Jewishnot grpmax-eligible	0.662%	151
African / African-American	0.264%	379
South Asian	0.186%	538
Middle Eastern	0.149%	671
East Asian	0.00446%	22,414

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: C2CD3
Protein: p.His240Asp
Coding: c.718C>G
MANE Select: NM_001286577
dbSNP: rs72984881
Type: single nucleotide variant
Location: chr11:74138957 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65

Full C2CD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD3 p.His240Arg Uncertain significance ★ ⚠ same residue
C2CD3 c.3911-2A>T Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg621Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Arg666Ter Pathogenic ★★ same type
C2CD3 p.Arg768Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 p.Tyr173Ter Pathogenic/Likely pathogenic ★★ same type
C2CD3 c.2085+5G>A Uncertain significance ★★ same type
C2CD3 c.4951+6C>T Uncertain significance ★★ 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/c2cd3-p-his240asp (accessed [today's date]).

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