Is MCPH1 p.Val76= (c.228G>T) pathogenic?

MCPH1 p.Val76= (c.228G>T) is classified Benign in MCPH1 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 83.7%, amr) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Val76= (c.228G>T)?

MCPH1 p.Val76= (c.228G>T) is associated with microcephaly 1, primary, autosomal recessive (ClinVar).

MCPH1 p.Val76=

Q: How common is MCPH1 p.Val76= (c.228G>T) in the general population?

MCPH1 p.Val76= (c.228G>T) is common (popmax 83.7%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.228G>T · rs2305022 · VCV158851

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 83.7%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

microcephaly 1, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.2	GERP -5
Overall
CADD	0.441	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 83.7% Admixed American · 50,082/59,858 alleles

Filtering AF 83.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 82.8%

Overall 78.2% 1,260,771/1,612,258 alleles · common exomes 1,154,498/1,460,924 · genomes 106,273/151,334 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	89%	1
Amishnot grpmax-eligible	85.8%	1
Admixed Americangrpmax	83.7%	1
European (non-Finnish)	80.2%	1
East Asian	78.5%	1
Remaining individualsnot grpmax-eligible	76.1%	1
South Asian	74.2%	1
Ashkenazi Jewishnot grpmax-eligible	68.9%	1
Middle Eastern	65.4%	2
African / African-American	43.3%	2

Finnish 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: MCPH1
Protein: p.Val76=
Coding: c.228G>T
MANE Select: NM_024596
dbSNP: rs2305022
Type: single nucleotide variant
Location: chr8:6414878 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 76: the brct 1 domain; 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 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
MCPH1 p.Ala702Val 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-val76 (accessed [today's date]).

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