Is MCPH1 p.Ala2Val (c.5C>T) pathogenic?

MCPH1 p.Ala2Val (c.5C>T) is classified Uncertain significance in MCPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-10). AlphaMissense: ambiguous (0.3716); Very rare (popmax 0.00267%, afr).

How common is MCPH1 p.Ala2Val (c.5C>T) in the general population?

MCPH1 p.Ala2Val (c.5C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about MCPH1 p.Ala2Val (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.3716) — an in-silico prediction, not a clinical call.

MCPH1 p.Ala2Val

c.5C>T · rs759488210 · VCV1376075

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3716 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3716	ambiguous
REVEL	0.047	moderately benign-leaning
SaProt	LLR -9.25	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.76	GERP -1.2, phastCons 0.99
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	20.9	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 0.00267% African / African-American · 2/75,036 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,611,902 alleles · very rare exomes 3/1,459,606 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,518
South Asian	0.0011%	90,892

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_024596
dbSNP: rs759488210
Type: single nucleotide variant
Location: chr8:6406672 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 2: the brct 1 domain; an α-helix

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

Similar variants

MCPH1 p.Ala2= Likely benign ★ same residue
MCPH1 c.321+2T>C Likely pathogenic ★★ same type
MCPH1 c.322-1G>C Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Gln199Ter Pathogenic ★★ same type
MCPH1 p.Gln386Ter Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Gly245Ter Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Leu542Ter Pathogenic/Likely pathogenic ★★ same type
MCPH1 p.Lys105Ter Pathogenic/Likely pathogenic ★★ 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/mcph1-p-ala2val (accessed [today's date]).

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