Is DIP2C p.Met616Ile (c.1848G>A) pathogenic?

DIP2C p.Met616Ile (c.1848G>A) is classified Uncertain significance in DIP2C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-19). AlphaMissense: likely pathogenic (0.8454); Very rare (popmax 0.00338%, amr).

How common is DIP2C p.Met616Ile (c.1848G>A) in the general population?

DIP2C p.Met616Ile (c.1848G>A) is very rare (popmax 0.00338%, amr) (gnomAD).

What do computational predictors say about DIP2C p.Met616Ile (c.1848G>A)?

AlphaMissense predicts likely pathogenic (score 0.8454) — an in-silico prediction, not a clinical call.

DIP2C p.Met616Ile

c.1848G>A · rs763608062 · VCV2784257

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8454 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00338%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8454	likely pathogenic
REVEL	0.32	indeterminate
SaProt	LLR -6.90	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 54 kb · p 2.7e-23 · regional, not allelic
Overall
CADD	22.3	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 0.00338% Admixed American · 2/59,130 alleles

Filtering AF 0.000561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00021%

Overall 0.000206% 3/1,457,860 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00338%	29,565
European (non-Finnish)	8.48e-05%	1,178,716

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.Met616Ile
Coding: c.1848G>A
MANE Select: NM_014974
dbSNP: rs763608062
Type: single nucleotide variant
Location: chr10:384055 (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-met616ile (accessed [today's date]).

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