Is MDC1 p.Ser516Pro (c.1546T>C) pathogenic?

MDC1 p.Ser516Pro (c.1546T>C) is classified Uncertain significance in MDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.2156); Very rare (popmax 0.00333%, amr).

How common is MDC1 p.Ser516Pro (c.1546T>C) in the general population?

MDC1 p.Ser516Pro (c.1546T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about MDC1 p.Ser516Pro (c.1546T>C)?

AlphaMissense predicts likely benign (score 0.2156) — an in-silico prediction, not a clinical call.

MDC1 p.Ser516Pro

c.1546T>C · VCV4550610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2156 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2156	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -7.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 15 kb · p 1.9e-17 · regional, not allelic
Overall
CADD	22.3	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 0.00333% Admixed American · 2/60,024 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,044 alleles · very rare exomes 2/1,460,770 · genomes 0/152,274 · joint denominator

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.Ser516Pro
Coding: c.1546T>C
MANE Select: NM_014641
Type: single nucleotide variant
Location: chr6:30712396 (GRCh38)
Gene constraint: LOEUF 0.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 40.39 · 12 PDB
Residue 516: the 'required for nuclear localization (nls1)' 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-ser516pro (accessed [today's date]).

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