Is HERC2 p.Ser3398= (c.10194A>G) pathogenic?

HERC2 p.Ser3398= (c.10194A>G) is classified Benign in HERC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-27). Common (popmax 99.4%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with developmental delay with autism spectrum disorder and gait instability.

What condition is associated with HERC2 p.Ser3398= (c.10194A>G)?

HERC2 p.Ser3398= (c.10194A>G) is associated with developmental delay with autism spectrum disorder and gait instability (ClinVar).

HERC2 p.Ser3398=

Q: How common is HERC2 p.Ser3398= (c.10194A>G) in the general population?

HERC2 p.Ser3398= (c.10194A>G) is common (popmax 99.4%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Developmental delay with autism spectrum disorder and gait instability inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.10194A>G · rs7494786 · VCV1225377

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 99.4%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

developmental delay with autism spectrum disorder and gait instability

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.56	phastCons 0.001
Overall
CADD	1.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 99.4% European (non-Finnish) · 1,169,916/1,177,076 alleles

Filtering AF 99.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.2%

Overall 97.4% 1,567,196/1,609,558 alleles · common exomes 1,426,259/1,457,258 · genomes 140,937/152,300 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	99.9%	1
European (non-Finnish)grpmax	99.4%	1
East Asian	98.8%	1
Amishnot grpmax-eligible	98%	1
Admixed American	97.3%	1
Ashkenazi Jewishnot grpmax-eligible	96.9%	1
Remaining individualsnot grpmax-eligible	96.1%	1
Middle Eastern	89%	1
South Asian	86.4%	1
African / African-American	77.8%	1

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: HERC2
Protein: p.Ser3398=
Coding: c.10194A>G
MANE Select: NM_004667
dbSNP: rs7494786
Type: single nucleotide variant
Location: chr15:28169519 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)

Full HERC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental delay with autism spectrum disorder and gait instability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Developmental delay with autism spectrum disorder and gait instability (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

HERC2 p.Arg1376Ter Pathogenic/Likely pathogenic ★★ same condition
HERC2 p.Ala200Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2582Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2671Gly Uncertain significance ★★ same condition
HERC2 p.Ala3439Thr Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala4253Thr Uncertain significance ★★ same condition
HERC2 p.Ala4345Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala876Val 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/herc2-p-ser3398 (accessed [today's date]).

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