Is DRAM2 p.Phe129Ser (c.386T>C) pathogenic?

DRAM2 p.Phe129Ser (c.386T>C) is classified Uncertain significance in DRAM2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-12-21). AlphaMissense: likely pathogenic (0.9485); Very rare (popmax 0.00051%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DRAM2 p.Phe129Ser (c.386T>C)?

DRAM2 p.Phe129Ser (c.386T>C) is associated with Inborn genetic diseases (ClinVar).

How common is DRAM2 p.Phe129Ser (c.386T>C) in the general population?

DRAM2 p.Phe129Ser (c.386T>C) is very rare (popmax 0.00051%, nfe) (gnomAD).

What do computational predictors say about DRAM2 p.Phe129Ser (c.386T>C)?

AlphaMissense predicts likely pathogenic (score 0.9485) — an in-silico prediction, not a clinical call.

DRAM2 p.Phe129Ser

c.386T>C · rs1387364883 · VCV1377626

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9485 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00051%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9485	likely pathogenic · top 9% in DRAM2
REVEL	0.659	pathogenic-leaning
SaProt	LLR -14.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 13 kb · p 0.69 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00051% European (non-Finnish) · 6/1,176,390 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000373% 6/1,607,184 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: DRAM2
Protein: p.Phe129Ser
Coding: c.386T>C
MANE Select: NM_001349884
dbSNP: rs1387364883
Type: single nucleotide variant
Location: chr1:111120647 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DRAM2 p.Phe129= Likely benign ★★ same residue
DRAM2 p.Arg260Gln Uncertain significance ★★ ⚠ same condition
DRAM2 p.Arg74Cys Uncertain significance ★★ ⚠ same condition
DRAM2 p.Gln145Lys Uncertain significance ★★ ⚠ same condition
DRAM2 p.Gly132Asp Uncertain significance ★★ ⚠ same condition
DRAM2 p.His194Arg Uncertain significance ★★ ⚠ same condition
DRAM2 p.His242Arg Uncertain significance ★★ ⚠ same condition
DRAM2 p.Ile227Val Uncertain significance ★★ ⚠ same condition

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-phe129ser (accessed [today's date]).

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