Is MCPH1 p.Pro828Ser (c.2482C>T) pathogenic?

MCPH1 p.Pro828Ser (c.2482C>T) is classified Benign in MCPH1 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0814); Common (popmax 39.2%, sas) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Pro828Ser (c.2482C>T)?

MCPH1 p.Pro828Ser (c.2482C>T) is associated with microcephaly 1, primary, autosomal recessive (ClinVar).

What do computational predictors say about MCPH1 p.Pro828Ser (c.2482C>T)?

AlphaMissense predicts likely benign (score 0.0814) — an in-silico prediction, not a clinical call.

MCPH1 p.Pro828Ser

Q: How common is MCPH1 p.Pro828Ser (c.2482C>T) in the general population?

MCPH1 p.Pro828Ser (c.2482C>T) is common (popmax 39.2%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2482C>T · rs1057091 · VCV21703

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0814 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 39.2%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 1, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.0814	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -6.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.95	GERP -3.8
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	3.483	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 39.2% South Asian · 35,697/90,988 alleles

Filtering AF 38.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 38.8%

Overall 30.2% 487,560/1,612,652 alleles · common exomes 447,083/1,460,592 · genomes 40,477/152,060 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	39.2%	3
Middle Eastern	34.2%	3
European (non-Finnish)	31%	3
Ashkenazi Jewishnot grpmax-eligible	30.9%	3
Remaining individualsnot grpmax-eligible	29.6%	3
Finnishnot grpmax-eligible	29.1%	3
Amishnot grpmax-eligible	29%	3
East Asian	26.6%	4
Admixed American	19.7%	5
African / African-American	19.2%	5

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: MCPH1
Protein: p.Pro828Ser
Coding: c.2482C>T
MANE Select: NM_024596
dbSNP: rs1057091
Type: single nucleotide variant
Location: chr8:6643023 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 828: the brct 3 domain; a UniProt-annotated variant site (in); an α-helix

Full MCPH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 1, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MCPH1 p.Pro828= Likely benign ★ same residue
MCPH1 c.321+2T>C Likely pathogenic ★★ same condition
MCPH1 c.322-1G>C Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Gln386Ter Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Gly245Ter Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Leu542Ter Pathogenic/Likely pathogenic ★★ same condition
MCPH1 p.Ser72Leu Pathogenic/Likely pathogenic ★★ same condition
MCPH1 c.1935+6T>C 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/mcph1-p-pro828ser (accessed [today's date]).

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