Is MDC1 p.Asp651= (c.1953C>T) pathogenic?

MDC1 p.Asp651= (c.1953C>T) is classified Likely benign in MDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-01). Ultra-rare (popmax 0.0894%, eas).

How common is MDC1 p.Asp651= (c.1953C>T) in the general population?

MDC1 p.Asp651= (c.1953C>T) is ultra-rare (popmax 0.0894%, eas) (gnomAD).

MDC1 p.Asp651=

c.1953C>T · VCV4873356

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0894%, eas)

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 2.1	phastCons 0.035
Overall
CADD	1.627	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0894% East Asian · 40/44,762 alleles

Filtering AF 0.0675% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0597%

Overall 0.0161% 258/1,597,834 alleles · ultra-rare exomes 233/1,445,552 · genomes 25/152,282 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.227%	441
East Asiangrpmax	0.0894%	1,119
South Asian	0.071%	1,409
Middle Eastern	0.0168%	5,964
Admixed American	0.00866%	11,552
European (non-Finnish)	0.000768%	130,288

Remaining individuals 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: MDC1
Protein: p.Asp651=
Coding: c.1953C>T
MANE Select: NM_014641
Type: single nucleotide variant
Location: chr6:30711989 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 40.39 · 12 PDB

Full MDC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MDC1 p.Gln1258= Likely benign ★★ same type
MDC1 p.Leu1207Pro Likely benign ★★ same type
MDC1 p.Ser1276= Benign/Likely benign ★★ same type
MDC1 p.Thr1261= Likely benign ★★ same type
MDC1 p.Arg1882Ter Pathogenic ★ same type
MDC1 p.Arg1993Ter Pathogenic ★ same type
MDC1 p.Met1Leu Pathogenic ★ same type
MDC1 p.Ala1017Thr 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/mdc1-p-asp651 (accessed [today's date]).

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