Is DRC12 p.Ala140Pro (c.418G>C) pathogenic?

DRC12 p.Ala140Pro (c.418G>C) is classified Uncertain significance in DRC12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.2756); Very rare (popmax 0.000593%, nfe).

How common is DRC12 p.Ala140Pro (c.418G>C) in the general population?

DRC12 p.Ala140Pro (c.418G>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about DRC12 p.Ala140Pro (c.418G>C)?

AlphaMissense predicts likely benign (score 0.2756) — an in-silico prediction, not a clinical call.

DRC12 p.Ala140Pro

c.418G>C · VCV4662101

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2756	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -11.74	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.006	GERP -0.33, phastCons 0.001
Regional constraint	o/e 0.91	unconstrained · MANE · 5,184 bp · p 0.14 · regional, not allelic
Overall
CADD	15.04	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 0.000593% European (non-Finnish) · 7/1,180,022 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,461,832 alleles · very rare

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: DRC12
Protein: p.Ala140Pro
Coding: c.418G>C
MANE Select: NM_001145018
Type: single nucleotide variant
Location: chr11:119190772 (GRCh38)
Structure: AlphaFold pLDDT 88.66

Full DRC12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DRC12 p.Ala140Gly Uncertain significance ★ ⚠ same residue
DRC12 p.Ala123Pro Uncertain significance ★ ⚠ same type
DRC12 p.Ala186Thr Uncertain significance ★ ⚠ same type
DRC12 p.Arg113Leu Uncertain significance ★ ⚠ same type
DRC12 p.Arg113Pro Uncertain significance ★ ⚠ same type
DRC12 p.Arg127Trp Uncertain significance ★ ⚠ same type
DRC12 p.Arg137Gln Uncertain significance ★ ⚠ same type
DRC12 p.Arg137Trp 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/drc12-p-ala140pro (accessed [today's date]).

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