Is OFD1 p.Val565Ala (c.1694T>C) pathogenic?

OFD1 p.Val565Ala (c.1694T>C) is classified Benign/Likely benign in OFD1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.1083); Rare (popmax 0.968%, sas); Associated with Simpson-Golabi-Behmel syndrome type 2.

What condition is associated with OFD1 p.Val565Ala (c.1694T>C)?

OFD1 p.Val565Ala (c.1694T>C) is associated with Simpson-Golabi-Behmel syndrome type 2, isolated cerebellar hypoplasia/agenesis, retinitis pigmentosa 23 (ClinVar).

How common is OFD1 p.Val565Ala (c.1694T>C) in the general population?

OFD1 p.Val565Ala (c.1694T>C) is rare (popmax 0.968%, sas) (gnomAD).

What do computational predictors say about OFD1 p.Val565Ala (c.1694T>C)?

AlphaMissense predicts likely benign (score 0.1083) — an in-silico prediction, not a clinical call.

OFD1 p.Val565Ala

c.1694T>C · rs529916753 · VCV412874

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1083 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.968%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Simpson-Golabi-Behmel syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.1083	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -6.89	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 1.9	GERP 5.8, phastCons 0.66
Regional constraint	o/e 0.93	unconstrained · MANE · 25 kb · p 0.12 · regional, not allelic
Overall
CADD	17.03	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 0.968% South Asian · 551/56,896 alleles

Filtering AF 0.901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.875%

Overall 0.0516% 625/1,210,590 alleles · rare exomes 577/1,097,953 · genomes 48/112,637 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.968%	103
Remaining individualsnot grpmax-eligible	0.0714%	1,400
Middle Eastern	0.0459%	2,178
European (non-Finnish)	0.00391%	25,577
African / African-American	0.00348%	28,733
Finnishnot grpmax-eligible	0.00214%	46,690

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: OFD1
Protein: p.Val565Ala
Coding: c.1694T>C
MANE Select: NM_003611
dbSNP: rs529916753
Type: single nucleotide variant
Location: chrX:13760154 (GRCh38)
Structure: AlphaFold pLDDT 68.41

Full OFD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Simpson-Golabi-Behmel syndrome type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated cerebellar hypoplasia/agenesis retinitis pigmentosa 23 Joubert syndrome 10 orofaciodigital syndrome I primary ciliary dyskinesia Joubert syndrome

Similar variants

OFD1 c.1411+1G>A Pathogenic ★★ same condition
OFD1 c.2600-1G>C Pathogenic/Likely pathogenic ★★ same condition
OFD1 p.Arg367Ter Pathogenic ★★ same condition
OFD1 p.Arg41Ter Pathogenic ★★ same condition
OFD1 p.Arg890Ter Pathogenic/Likely pathogenic ★★ same condition
OFD1 p.Arg909Ter Pathogenic/Likely pathogenic ★★ same condition
OFD1 p.Gln966Ter Pathogenic/Likely pathogenic ★★ same condition
OFD1 p.Tyr87Cys Pathogenic ★★ ⚠ 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/ofd1-p-val565ala (accessed [today's date]).

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