Is MCPH1 p.Arg171Ser (c.513G>T) pathogenic?

MCPH1 p.Arg171Ser (c.513G>T) is classified Benign in MCPH1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0911); Common (popmax 99.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 1, primary, autosomal recessive.

What condition is associated with MCPH1 p.Arg171Ser (c.513G>T)?

MCPH1 p.Arg171Ser (c.513G>T) is associated with microcephaly 1, primary, autosomal recessive (ClinVar).

What do computational predictors say about MCPH1 p.Arg171Ser (c.513G>T)?

AlphaMissense predicts likely benign (score 0.0911) — an in-silico prediction, not a clinical call.

MCPH1 p.Arg171Ser

Q: How common is MCPH1 p.Arg171Ser (c.513G>T) in the general population?

MCPH1 p.Arg171Ser (c.513G>T) is common (popmax 99.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.513G>T · rs2442513 · VCV1174812

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0911 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 99.2%, eas) — 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	0.0911	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -5.09	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 -1.5	GERP -3.2
Regional constraint	o/e 1.49	unconstrained · MANE · 236 kb · p 2.4e-54 · regional, not allelic
Overall
CADD	0.318	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 99.2% East Asian · 44,501/44,840 alleles

Filtering AF 98.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.4%

Overall 97.3% 1,569,728/1,612,852 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	99.2%	1
Finnishnot grpmax-eligible	98.8%	1
European (non-Finnish)	98.6%	1
Ashkenazi Jewishnot grpmax-eligible	98%	1
Admixed American	97.8%	1
Middle Eastern	97%	1
Remaining individualsnot grpmax-eligible	96.6%	1
Amishnot grpmax-eligible	95.7%	1
South Asian	95.5%	1
African / African-American	77.5%	1

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.Arg171Ser
Coding: c.513G>T
MANE Select: NM_024596
dbSNP: rs2442513
Type: single nucleotide variant
Location: chr8:6439029 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 9 PDB
Residue 171: a UniProt-annotated variant site (in)

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.Arg171= 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-arg171ser (accessed [today's date]).

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