Is DRAM2 p.Ala63Val (c.188C>T) pathogenic?

DRAM2 p.Ala63Val (c.188C>T) is classified Uncertain significance in DRAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-05). AlphaMissense: ambiguous (0.4328); Very rare (popmax 0.00224%, eas).

How common is DRAM2 p.Ala63Val (c.188C>T) in the general population?

DRAM2 p.Ala63Val (c.188C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about DRAM2 p.Ala63Val (c.188C>T)?

AlphaMissense predicts ambiguous (score 0.4328) — an in-silico prediction, not a clinical call.

DRAM2 p.Ala63Val

c.188C>T · rs145044841 · VCV1359209

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4328	ambiguous
REVEL	0.172	moderately benign-leaning
SaProt	LLR -9.62	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.28	donor loss, 11 bp away · masked 0 · deltas
Pangolin	Δ0.20	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 13 kb · p 0.69 · regional, not allelic
Overall
CADD	23.7	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 0.00224% East Asian · 1/44,704 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000412% 6/1,456,424 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,704
South Asian	0.0011%	90,562
European (non-Finnish)	0.00034%	293,872

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: DRAM2
Protein: p.Ala63Val
Coding: c.188C>T
MANE Select: NM_001349884
dbSNP: rs145044841
Type: single nucleotide variant
Location: chr1:111126238 (GRCh38)
Gene constraint: LOEUF 1.115 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.35

Full DRAM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DRAM2 p.Ala63= Likely benign ★★ same residue
DRAM2 c.340-2A>G Pathogenic/Likely pathogenic ★★ same type
DRAM2 c.518-1G>A Likely pathogenic ★★ same type
DRAM2 c.601-1G>A Likely pathogenic ★★ same type
DRAM2 p.Gln147Ter Pathogenic/Likely pathogenic ★★ same type
DRAM2 p.Trp165Ter Pathogenic ★★ same type
DRAM2 c.199+6T>G Uncertain significance ★★ same type
DRAM2 p.Ala39Thr 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/dram2-p-ala63val (accessed [today's date]).

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