Is IHH p.Ser407= (c.1221C>T) pathogenic?

IHH p.Ser407= (c.1221C>T) is classified Likely benign in IHH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-06). Ultra-rare (popmax 0.0165%, mid); Associated with brachydactyly type A1.

What condition is associated with IHH p.Ser407= (c.1221C>T)?

IHH p.Ser407= (c.1221C>T) is associated with brachydactyly type A1 (ClinVar).

How common is IHH p.Ser407= (c.1221C>T) in the general population?

IHH p.Ser407= (c.1221C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

IHH p.Ser407=

c.1221C>T · rs774963881 · VCV735057

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

brachydactyly type A1

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 -4.8	GERP -4.7
Overall
CADD	0.214	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,054 alleles

Filtering AF 0.00705% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00392% 62/1,583,274 alleles · ultra-rare exomes 52/1,431,052 · genomes 10/152,222 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,054
Admixed American	0.0144%	6,966
African / African-American	0.00946%	10,576
East Asian	0.00703%	14,220
Remaining individualsnot grpmax-eligible	0.00652%	15,333
Ashkenazi Jewishnot grpmax-eligible	0.00345%	29,026
European (non-Finnish)	0.00317%	31,500
South Asian	0.00115%	87,120

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: IHH
Protein: p.Ser407=
Coding: c.1221C>T
MANE Select: NM_002181
dbSNP: rs774963881
Type: single nucleotide variant
Location: chr2:219055222 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.94 (gnomAD)
Structure: AlphaFold pLDDT 84.84 · 8 PDB

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

Disease context

brachydactyly type A1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IHH p.Asp100Asn Pathogenic ★★ same condition
IHH c.*423G>A Uncertain significance ★★ same condition
IHH p.Arg217Cys Uncertain significance ★★ ⚠ same condition
IHH p.Arg267Gly Uncertain significance ★★ ⚠ same condition
IHH p.Arg390His Uncertain significance ★★ ⚠ same condition
IHH p.Asn161Ser Uncertain significance ★★ ⚠ same condition
IHH p.Val304Leu Uncertain significance ★★ ⚠ same condition
IHH c.315+8C>T Benign/Likely benign ★★ 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/ihh-p-ser407 (accessed [today's date]).

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