Is MCPH1 p.Val50Ile (c.148G>A) pathogenic?

MCPH1 p.Val50Ile (c.148G>A) is classified Uncertain significance in MCPH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-08-10). AlphaMissense: likely benign (0.1728); Ultra-rare (popmax 0.0164%, mid); Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Val50Ile (c.148G>A)?

MCPH1 p.Val50Ile (c.148G>A) is associated with microcephaly 1, primary, autosomal recessive, microcephaly (ClinVar).

How common is MCPH1 p.Val50Ile (c.148G>A) in the general population?

MCPH1 p.Val50Ile (c.148G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about MCPH1 p.Val50Ile (c.148G>A)?

AlphaMissense predicts likely benign (score 0.1728) — an in-silico prediction, not a clinical call.

MCPH1 p.Val50Ile

c.148G>A · rs779924077 · VCV813531

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1728 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

microcephaly 1, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.1728	likely benign
REVEL	0.596	indeterminate
SaProt	LLR -9.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	26.9	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 · 1/6,080 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00186% 30/1,613,628 alleles · ultra-rare exomes 28/1,461,552 · genomes 2/152,076 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
East Asian	0.00668%	14,959
Remaining individualsnot grpmax-eligible	0.0032%	31,233
European (non-Finnish)	0.00195%	51,297
African / African-American	0.00134%	74,884

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.Val50Ile
Coding: c.148G>A
MANE Select: NM_024596
dbSNP: rs779924077
Type: single nucleotide variant
Location: chr8:6414798 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 50: the brct 1 domain; a β-strand

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

Also linked: microcephaly

Similar variants

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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-val50ile (accessed [today's date]).

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