Is DIP2C p.Pro416= (c.1248G>A) pathogenic?

DIP2C p.Pro416= (c.1248G>A) is classified Benign in DIP2C (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). Common (popmax 99.9%, sas) — too common for a highly-penetrant pathogenic allele.

DIP2C p.Pro416=

Q: How common is DIP2C p.Pro416= (c.1248G>A) in the general population?

DIP2C p.Pro416= (c.1248G>A) is common (popmax 99.9%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1248G>A · rs6560837 · VCV1545960

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 99.9%, sas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.3	GERP -3.7
Overall
CADD	0.932	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 99.9% South Asian · 91,003/91,072 alleles

Filtering AF 99.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.6%

Overall 99.4% 1,603,360/1,613,718 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	100%	1
Finnishnot grpmax-eligible	100%	1
South Asiangrpmax	99.9%	1
European (non-Finnish)	99.8%	1
Admixed American	99.1%	1
Remaining individualsnot grpmax-eligible	98.8%	1
East Asian	98.5%	1
Middle Eastern	98%	1
Ashkenazi Jewishnot grpmax-eligible	97.5%	1
African / African-American	93.2%	1

Amish 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: DIP2C
Protein: p.Pro416=
Coding: c.1248G>A
MANE Select: NM_014974
dbSNP: rs6560837
Type: single nucleotide variant
Location: chr10:399121 (GRCh38)
Gene constraint: LOEUF 0.235 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.64

Full DIP2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DIP2C p.Ala1066Thr Uncertain significance ★★ ⚠ same type
DIP2C p.Ala1066Val Uncertain significance ★★ ⚠ same type
DIP2C p.Ala1101Val Uncertain significance ★★ ⚠ same type
DIP2C p.Ala1155Thr Uncertain significance ★★ ⚠ same type
DIP2C p.Ala1466Thr Uncertain significance ★★ ⚠ same type
DIP2C p.Ala193Val Uncertain significance ★★ ⚠ same type
DIP2C p.Ala422Thr Uncertain significance ★★ ⚠ same type
DIP2C p.Ala71Thr 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/dip2c-p-pro416 (accessed [today's date]).

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