Is MDC1 p.Pro109Ser (c.325C>T) pathogenic?

MDC1 p.Pro109Ser (c.325C>T) is classified Uncertain significance in MDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). AlphaMissense: likely benign (0.3368); Ultra-rare (popmax 0.0164%, mid).

How common is MDC1 p.Pro109Ser (c.325C>T) in the general population?

MDC1 p.Pro109Ser (c.325C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about MDC1 p.Pro109Ser (c.325C>T)?

AlphaMissense predicts likely benign (score 0.3368) — an in-silico prediction, not a clinical call.

MDC1 p.Pro109Ser

c.325C>T · VCV3393983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3368 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3368	likely benign
REVEL	0.535	indeterminate
SaProt	LLR -8.73	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 15 kb · p 1.9e-17 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,612,798 alleles · ultra-rare exomes 5/1,460,774 · genomes 1/152,024 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.000424%	236,000

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.Pro109Ser
Coding: c.325C>T
MANE Select: NM_014641
Type: single nucleotide variant
Location: chr6:30713995 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 40.39 · 12 PDB
Residue 109: the 'interaction with chek2' region; the 'interaction with the mrn complex' region

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-pro109ser (accessed [today's date]).

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